Polycyclic pyridone derivative having integrase inhibitory activity

ABSTRACT

The present invention relates to a novel compound having an antiviral effect, more specifically, a pyridone derivative having HIV integrase inhibitory activity, and a medicament containing the same, in particular, an anti-HIV agent. The compound of the present invention has integrase inhibitory activity and/or cell proliferation inhibitory activity against viruses, in particular, HIV and drug-resistant strains thereof. Thus, the compound is useful in preventing or treating various diseases, viral infections (for example, AIDS), and the like in which integrase participates.

TECHNICAL FIELD

The present invention relates to novel compounds having antiviralactivity, more particularly, polycyclic pyridone derivatives having HIVintegrase inhibitory activity; and a medicament containing the same,particularly an anti-HIV agent.

BACKGROUND ART

Among viruses, human immunodeficiency virus (hereafter, referred to asHIV), a kind of retrovirus, is known to cause acquired immunodeficiencysyndrome (hereafter, referred to as AIDS). The therapeutic agent forAIDS is mainly selected from a group of reverse transcriptase inhibitors(e.g., AZT, 3TC, etc.) and protease inhibitors (e.g., Indinavir, etc.),but they are proved to be accompanied by the following problems: sideeffects such as nephropathy, the emergence of resistant viruses, and thelike. Thus, the development of anti-HIV agents having the othermechanisms of action therefrom has been desired.

On the other hand, currently, a multiple combination therapy is reportedto be efficient in treatment for AIDS because of the frequent emergenceof the resistant mutant virus. Two kinds of reverse transcriptaseinhibitors and protease inhibitors are clinically used as an anti-HIVagent; however agents having the same mechanism of action often exhibitcross-resistance or only an additional activity. Therefore, developmentof anti-HIV agents having the other mechanism of action is desired.

Under the circumstances above, an integrase inhibitor has been focusedon as an anti-HIV agent having a novel mechanism of action (PatentDocuments 1 and 2). As an anti-HIV agent having such a mechanism ofaction, known are carbamoyl-substituted hydroxypyrimidinone derivative(Patent Document 3) and carbamoyl-substituted hydroxypyrrolidionederivative (Patent Document 4). Further, a patent application concerningcarbamoyl-substituted hydroxypyridone derivative has been filed (PatentDocument 5, Example 8).

Further, other known carbamoylpyridone derivatives include5-alkoxypyridine-3-carboxamide derivatives and γ-pyrone-3-carboxamidederivatives, which are a plant growth inhibitor or herbicide (PatentDocuments 6-8).

Furthermore, other HIV integrase inhibitors include nitrogen-containingcondensed cyclic compounds (Patent Document 9).

Moreover, other HIV integrase inhibitors are known, and in suchcompounds, the terminal of an amide side chain is aryl (Patent Documents10 and 11). In addition, a bicyclic HIV integrase inhibitor is known(Patent Document 12).

Further, the present applicant filed a patent application of ananti-influenza agent comprising a nitrogen-containing condensed cycliccompound as an active ingredient (Patent Document 13).

In addition, the present applicant filed a patent application of an HIVintegrase inhibitor comprising a nitrogen-containing condensed cycliccompound as an active ingredient (Patent Document 14 and 15).

Moreover, HIV integrase inhibitors comprising a nitrogen-containingcondensed cyclic compound having a spiro cycle or a bridge as an activeingredient were filed (Patent Documents 16 to 27).

PRIOR ART REFERENCES Patent Document

[Patent Document 1] International Publication No. 03/016275 pamphlet[Patent Document 2] International Publication No. 2004/024693 pamphlet[Patent Document 3] International Publication No. 03/035076 pamphlet[Patent Document 4] International Publication No. 2004/004657 pamphlet

[Patent Document 5] Japanese Laid-Open Publication No. 2004-244320

[Patent Document 6] Japanese Laid-Open Publication No. H2-108668[Patent Document 7] Japanese Laid-Open Publication No. H2-108683[Patent Document 8] Japanese Laid-Open Publication No. H2-96506[Patent Document 9] International Publication No. 2005/016927 pamphlet[Patent Document 10] International Publication No. 2006/116764 pamphlet[Patent Document 11] International Publication No. 2007/049675 pamphlet[Patent Document 12] International Publication No. 2011/105590 pamphlet[Patent Document 13] International Publication No. 2010/147068 pamphlet[Patent Document 14] International Publication No. 2011/129095 pamphlet[Patent Document 15] International Publication No. 2013/054862 pamphlet[Patent Document 16] International Publication No. 2014/099586 pamphlet[Patent Document 17] International Publication No. 2014/100323 pamphlet[Patent Document 18] International Publication No. 2014/104279 pamphlet[Patent Document 19] International Publication No. 2014/172188 pamphlet[Patent Document 20] International Publication No. 2014/183532 pamphlet[Patent Document 21] International Publication No. 2014/200880 pamphlet[Patent Document 22] International Publication No. 2015/039348 pamphlet[Patent Document 23] International Publication No. 2015/048363 pamphlet[Patent Document 24] International Publication No. 2015/089847 pamphlet[Patent Document 25] International Publication No. 2015/095258 pamphlet[Patent Document 26] International Publication No. 2015/006731 pamphlet[Patent Document 27] International Publication No. 2015/006733 pamphlet

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

Under such the circumstances, the development of a novel integraseinhibitor has been desired.

Means to Solve the Problems

The present inventors intensively studied to find that a novel pyridonederivative has potent HIV integrase inhibitory activity. Moreover, thepresent inventors have discovered that a compound of the presentinvention and a medicament containing the same are useful as anantiviral agent (e.g., antiretroviral agent, anti-HIV agent, anti-HTLV-1(Human T cell leukemia virus type 1) agent, anti-FIV (Felineimmunodeficiency virus) agent, anti-SIV (Simian immunodeficiency virus)agent), especially an anti-HIV agent, an anti-AIDS agent, a therapeuticfor associated diseases, or the like, to accomplish the presentinvention shown below.

[1] A compound represented by the following formula (I-1) or (I-2), orits pharmaceutically acceptable salt:

wherein Q is a substituted or unsubstituted carbocyclyl or substitutedor unsubstituted heterocyclyl;

A ring is a substituted or unsubstituted heterocycle;

D ring is a substituted or unsubstituted heterocycle;

R³ is a hydrogen, halogen, hydroxy, substituted or unsubstituted loweralkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy,substituted or unsubstituted lower alkenyloxy, substituted orunsubstituted aryl, substituted or unsubstituted aryloxy, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedheterocyclyloxy, or substituted or unsubstituted amino;

R⁸ is a hydrogen, halogen, hydroxy, substituted or unsubstituted loweralkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy,substituted or unsubstituted lower alkenyloxy, substituted orunsubstituted aryl, substituted or unsubstituted aryloxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted heterocyclyloxyor substituted or unsubstituted amino;

R¹⁴ and R^(X) are each independently, hydrogen, substituted orunsubstituted lower alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkyl lower alkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy,substituted or unsubstituted lower alkenyloxy, substituted orunsubstituted aryl, substituted or unsubstituted aryl lower alkyl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclyl lower alkyl,substituted or unsubstituted heterocyclyloxy, substituted orunsubstituted phosphoric acid residue, aryl substituted with substitutedor unsubstituted phosphoric acid residue, hydroxy substituted withsubstituted or unsubstituted phosphoric acid residue, amino substitutedwith substituted or unsubstituted phosphoric acid residue, lower alkylsubstituted with substituted or unsubstituted phosphoric acid residue(wherein a heteroatom group selected from the group consisting of O, S,SO, SO₂, NR⁵, —N═ and ═N— may intervene in the lower alkyl), hydroxy,substituted or unsubstituted amino, substituted or unsubstituted loweralkylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl,substituted or unsubstituted cycloalkyl lower alkylcarbonyl, substitutedor unsubstituted lower alkoxycarbonyl, substituted or unsubstitutedarylcarbonyl, substituted or unsubstituted aryl lower alkylcarbonyl,substituted or unsubstituted aryloxycarbonyl, substituted orunsubstituted heterocyclylcarbonyl, substituted or unsubstitutedheterocyclyl lower alkylcarbonyl, substituted or unsubstitutedheterocyclyloxycarbonyl or substituted or unsubstituted aminocarbonyl;

R⁵ is a hydrogen, substituted or unsubstituted lower alkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyllower alkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkoxy, substituted or unsubstituted aryl,substituted or unsubstituted aryl lower alkyl, substituted orunsubstituted aryloxy, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclyl lower alkyl, substituted orunsubstituted heterocyclyloxy, hydroxy, substituted or unsubstitutedamino, substituted or unsubstituted phosphoric acid residue, arylsubstituted with substituted or unsubstituted phosphoric acid residue,hydroxy substituted with substituted or unsubstituted phosphoric acidresidue, amino substituted with substituted or unsubstituted phosphoricacid residue or lower alkyl substituted with substituted orunsubstituted phosphoric acid residue (wherein a heteroatom groupselected from the group consisting of CO, O, S, SO, SO₂, NR^(a) (R^(a)is a hydrogen or lower alkyl), —N═ and ═N— may intervene in the loweralkyl);

or R¹⁴ and R^(X) may be taken together with neighboring atoms to formsubstituted or unsubstituted spiro ring;

the broken line represents the presence or absence of a bond;

when the broken line adjacent to the carbon atom connected with R^(x)represents the presence of a bond, R^(x) is absence;

when the broken line adjacent to the carbon atom connected with R⁸represents the presence of a bond, R⁸ is absence;

both the broken lines adjacent to the carbon atom connected with R⁸cannot represent the presence of a bond at the same time; and

provided that the following compounds are excluded:

[2] The compound represented by the following formula (I-1) or itspharmaceutically acceptable salt according to the above item [1]:

wherein each symbol is defined as the same above item [1].[3] The compound or its pharmaceutically acceptable salt according tothe above item [2], wherein A ring is represented by any ine of thefollowing rings:

wherein Z¹, Z², Z³, Z⁴ and Z⁵ are each independently CR¹R², CR¹, O, S,SO, SO₂, N or NR¹⁹;

or Z¹ and Z³, Z¹ and Z⁴, Z¹ and Z⁵, Z² and Z⁴, Z² and Z⁵, or Z³ and Z⁵may be taken together to form substituted or unsubstituted (C2-C4)bridge;

R¹ and R² are each independently, hydrogen, halogen, substituted orunsubstituted lower alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkyl lower alkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy,substituted or unsubstituted lower alkenyloxy, substituted orunsubstituted aryl, substituted or unsubstituted aryl lower alkyl,substituted or unsubstituted aryl oxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclyl lower alkyl,substituted or unsubstituted heterocyclyloxy, substituted orunsubstituted phosphoric acid residue, aryl substituted with substitutedor unsubstituted phosphoric acid residue, hydroxy substituted withsubstituted or unsubstituted phosphoric acid residue, amino substitutedwith substituted or unsubstituted phosphoric acid residue, lower alkylsubstituted with substituted or unsubstituted phosphoric acid residue(wherein a heteroatom group selected from the group consisting of O, S,SO, SO₂, NR⁵ (wherein R⁵ is defined as the same above item [1]), —N═ and═N— may intervene in the lower alkyl), hydroxy, substituted orunsubstituted amino, substituted or unsubstituted lower alkylcarbonyl,substituted or unsubstituted cycloalkylcarbonyl, substituted orunsubstituted cycloalkyl lower alkylcarbonyl, substituted orunsubstituted lower alkoxycarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted aryl lower alkylcarbonyl,substituted or unsubstituted aryl oxycarbonyl, substituted orunsubstituted heterocyclylcarbonyl, substituted or unsubstitutedheterocyclyl lower alkylcarbonyl, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstituted aminocarbonyl,substituted or unsubstituted ureido or substituted or unsubstitutedthioureido;

or R¹ and R² may be taken together to form oxo, thioxo or substituted orunsubstituted spiro ring;

R¹⁹ is a hydrogen, substituted or unsubstituted lower alkyl, substitutedor unsubstituted lower alkenyl, substituted or unsubstituted loweralkylcarbonyl or substituted or unsubstituted lower alkylsulfonyl;

the broken line represents the presence or absence of a bond; and

R⁸ is defined as the same above item [1].

[4] The compound or its pharmaceutically acceptable salt according tothe above item [2], wherein A ring is represented by any one of thefollowing rings:

wherein E ring is substituted or unsubstituted carbocycle or substitutedor unsubstituted heterocycle;

Z¹, Z², Z³, Z⁴ and Z⁵ are each independently CR¹R², CR¹, C, O, S, SO,SO₂, N or NR¹⁹ (when Z¹, Z², Z³, Z⁴ or Z⁵ is/are constituent atom(s) ofE ring, Z¹, Z², Z³, Z⁴ and Z⁵ are each independently CR¹, C or N);

or Z¹ and Z³, Z¹ and Z⁴, Z¹ and Z⁵, Z² and Z⁴, Z² and Z⁵, or Z³ and Z⁵may be taken together to form substituted or unsubstituted (C2-C4)bridge;

R¹ and R² are each independently hydrogen, halogen, substituted orunsubstituted lower alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkyl lower alkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy,substituted or unsubstituted lower alkenyloxy, substituted orunsubstituted aryl, substituted or unsubstituted aryl lower alkyl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclyl lower alkyl,substituted or unsubstituted heterocyclyloxy, substituted orunsubstituted phosphoric acid residue, aryl substituted with substitutedor unsubstituted phosphoric acid residue, hydroxy substituted withsubstituted or unsubstituted phosphoric acid residue, amino substitutedwith substituted or unsubstituted phosphoric acid residue, lower alkylsubstituted with substituted or unsubstituted phosphoric acid residue(wherein a heteroatom group selected from the group consisting of O, S,SO, SO₂, NR⁵ (wherein R⁵ is defined as the same above item [1]), —N═ and═N— may intervene in the lower alkyl), hydroxy, substituted orunsubstituted amino, substituted or unsubstituted lower alkylcarbonyl,substituted or unsubstituted cycloalkylcarbonyl, substituted orunsubstituted cycloalkyl lower alkylcarbonyl, substituted orunsubstituted lower alkoxycarbonyl, substituted or unsubstitutedarylcarbonyl, substituted or unsubstituted aryl lower alkylcarbonyl,substituted or unsubstituted aryloxycarbonyl, substituted orunsubstituted heterocyclylcarbonyl, substituted or unsubstitutedheterocyclyl lower alkylcarbonyl, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstituted aminocarbonyl,substituted or unsubstituted ureido or substituted or unsubstitutedthioureido;

or R¹ and R² may be taken together to form oxo, thioxo or substituted orunsubstituted spiro ring;

R¹⁹ is a hydrogen, substituted or unsubstituted lower alkyl, substitutedor unsubstituted lower alkenyl, substituted or unsubstituted loweralkylcarbonyl or substituted or unsubstituted lower alkylsulfonyl;

R⁸ is defined as the same above item [1]; and

the broken line represents the presence or absence of a bond;

[5] The compound or its pharmaceutically acceptable salt according tothe above item [4], wherein E ring is substituted or unsubstituted 4- to7-membered carbocycle or substituted or unsubstituted 4- to 7-memberedheterocycle.[6] The compound represented by the following formula (I-1-1) or(I-2-1), or its pharmaceutically acceptable salt according to the aboveitem [2]:

wherein X is CR^(9a)R^(9b), NR¹⁰, O or S;

R^(5a), R^(5b), R^(6a), R^(6b), R^(7a), R^(7b), R⁸, R^(9a), R^(9b) andR¹⁰ are each independently, hydrogen, halogen, substituted orunsubstituted lower alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkyl lower alkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy,substituted or unsubstituted lower alkenyloxy, substituted orunsubstituted aryl, substituted or unsubstituted aryl lower alkyl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclyl lower alkyl,substituted or unsubstituted heterocyclyloxy, substituted orunsubstituted phosphoric acid residue, aryl substituted with substitutedor unsubstituted phosphoric acid residue, hydroxy substituted withsubstituted or unsubstituted phosphoric acid residue, amino substitutedwith substituted or unsubstituted phosphoric acid residue, lower alkylsubstituted with substituted or unsubstituted phosphoric acid residue(wherein a heteroatom group selected from the group consisting of O, S,SO, SO₂, NR⁵ (wherein R⁵ is defined as the same above item [1]), —N═ and═N— may intervene in the lower alkyl), hydroxy, substituted orunsubstituted amino, substituted or unsubstituted lower alkylcarbonyl,substituted or unsubstituted cycloalkylcarbonyl, substituted orunsubstituted cycloalkyl lower alkylcarbonyl, substituted orunsubstituted lower alkoxycarbonyl, substituted or unsubstitutedarylcarbonyl, substituted or unsubstituted aryl lower alkylcarbonyl,substituted or unsubstituted aryloxycarbonyl, substituted orunsubstituted heterocyclylcarbonyl, substituted or unsubstitutedheterocyclyl lower alkylcarbonyl, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstituted aminocarbonyl,substituted or unsubstituted ureido or substituted or unsubstitutedthioureido;

R^(5a) and R^(5b), R^(6a) and R^(6b), R^(7a) and R^(7b), and/or R^(9a)and R^(9b) may be taken together to form oxo, thioxo or substituted orunsubstituted spiro ring;

or R^(5b) and R^(6b), R^(6b) and R^(7b), and/or R^(7b) and R^(9b) may betaken together with neighboring atoms to form substituted orunsubstituted carbocycle or substituted or unsubstituted heterocycleand/or R^(5b) and R^(7b), R^(5b) and R⁸, R^(5b) and R^(9b), R^(6b) andR⁸, R^(6b) and R^(9b), or R^(7b) and R⁸ may be taken together to formsubstituted or unsubstituted (C2-C4) bridge;

or R^(5b) and R¹⁰ may be taken together with neighboring atoms to formsubstituted or unsubstituted heterocycle or R^(6b) and R¹⁰, or R^(7b)and R¹⁰ may be taken together to form substituted or unsubstituted(C2-C4) bridge;

R^(x) is a hydrogen; and

the other symbols are defined as the same above item [1].

[7] The compound or its pharmaceutically acceptable salt according tothe above item [6], wherein X is CR^(9a)R^(9b), O or S.[8] The compound or its pharmaceutically acceptable salt according tothe above item [6] or [7], wherein R^(5a) is hydrogen, halogen, hydroxy,substituted or unsubstituted lower alkyl or substituted or unsubstitutedlower alkoxy.[9] The compound or its pharmaceutically acceptable salt according toany one of the above items [6] to [8], wherein R^(5b) is hydrogen.[10] The compound or its pharmaceutically acceptable salt according toany one of the above items [6] to [9], wherein R^(6a) is a hydrogen,halogen, hydroxy, substituted or unsubstituted lower alkyl orsubstituted or unsubstituted lower alkoxy.[11] The compound or its pharmaceutically acceptable salt according toany one of the above items [6] to [10], wherein R^(6b) is hydrogen.[12] The compound or its pharmaceutically acceptable salt according toany one of the above items [6] to [11], wherein R^(7a) is a hydrogen,halogen, hydroxy, substituted or unsubstituted lower alkyl orsubstituted or unsubstituted lower alkoxy.[13] The compound or its pharmaceutically acceptable salt according toany one of the above items [6] to [12], wherein R⁷ b is hydrogen.[14] The compound or its pharmaceutically acceptable salt according toany one of the above items [6] to [13], wherein R⁸ is hydrogen.[15] The compound or its pharmaceutically acceptable salt according toany one of the above items [6] to [14], wherein R^(9a) is a hydrogen,halogen, hydroxy, substituted or unsubstituted lower alkyl orsubstituted or unsubstituted lower alkoxy.[16] The compound or its pharmaceutically acceptable salt according toany one of the above items [6] to [15], wherein R^(9b) is hydrogen.[17] The compound represented by any one of the following formula, orits pharmaceutically acceptable salt according to the above item [1]:

wherein each Q is defined as the same above item [1].[18] The compound represented by any one of the following formula, orits pharmaceutically acceptable salt according to the above item [1]:

wherein each Q is defined the same above item [1].[19] The compound represented by the following formula (I-2) or itspharmaceutically acceptable salt according to the above item [1]:

wherein each symbol is defined as the same above item [1].[20] A compound represented by the following formula (I-3), or itspharmaceutically acceptable salt:

wherein Q is substituted or unsubstituted carbocyclyl or substituted orunsubstituted heterocyclyl;

the broken line represents the presence or absence of a bond;

when either one of B¹ and B² is CR²⁰R²¹ and the other is NR²², thebroken line represents the absence of a bond; and R²⁰ and R²² may betaken together with the neighboring atoms to form substituted orunsubstituted heterocycle;

when B² is NR²², R⁴ and R²² may be taken together with the neighboringatoms to form substituted or unsubstituted heterocycle;

when B² is CR²⁰R²¹, R⁴ and R²¹ may be taken together with theneighboring atoms to form substituted or unsubstituted heterocycle; or

when either one of B¹ and B² is CR²³ and the other is N, the broken linerepresents the presence of a bond; when B² is CR²³, R⁴ and R²³ may betaken together with the neighboring atoms to form substituted orunsubstituted heterocycle;

R²⁰, R²¹, R²² and R²³ are each independently, hydrogen, halogen,substituted or unsubstituted lower alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkyl lower alkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedlower alkoxy, substituted or unsubstituted lower alkenyloxy, substitutedor unsubstituted aryl, substituted or unsubstituted aryl lower alkyl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclyl lower alkyl,substituted or unsubstituted heterocyclyloxy, substituted orunsubstituted phosphoric acid residue, aryl substituted with substitutedor unsubstituted phosphoric acid residue, hydroxy substituted withsubstituted or unsubstituted phosphoric acid residue, amino substitutedwith substituted or unsubstituted phosphoric acid residue, lower alkylsubstituted with substituted or unsubstituted phosphoric acid residue(wherein a heteroatom group selected from the group consisting of O, S,SO, SO₂, NR⁵ (wherein R⁵ is independently selected from the samesubstituent group as R⁴), —N═ and ═N— may intervene in the lower alkyl),hydroxy, substituted or unsubstituted amino, substituted orunsubstituted lower alkylcarbonyl, substituted or unsubstitutedcycloalkylcarbonyl, substituted or unsubstituted cycloalkyl loweralkylcarbonyl, substituted or unsubstituted lower alkoxycarbonyl,substituted or unsubstituted arylcarbonyl, substituted or unsubstitutedaryl lower alkylcarbonyl, substituted or unsubstituted aryloxycarbonyl,substituted or unsubstituted heterocyclylcarbonyl, substituted orunsubstituted heterocyclyl lower alkylcarbonyl, substituted orunsubstituted heterocyclyloxycarbonyl, substituted or unsubstitutedaminocarbonyl, substituted or unsubstituted ureido or substituted orunsubstituted thioureido;

R³ is hydrogen, halogen, hydroxy, substituted or unsubstituted loweralkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy,substituted or unsubstituted lower alkenyloxy, substituted orunsubstituted aryl, substituted or unsubstituted aryloxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted heterocyclyloxyor substituted or unsubstituted amino;

R⁴ is hydrogen, substituted or unsubstituted lower alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl loweralkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkoxy, substituted or unsubstituted aryl,substituted or unsubstituted aryl lower alkyl, substituted orunsubstituted aryloxy, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclyl lower alkyl, substituted orunsubstituted heterocyclyloxy, hydroxy, substituted or unsubstitutedamino, substituted or unsubstituted phosphoric acid residue, arylsubstituted with substituted or unsubstituted phosphoric acid residue,hydroxy substituted with substituted or unsubstituted phosphoric acidresidue, amino substituted with substituted or unsubstituted phosphoricacid residue or lower alkyl substituted with substituted orunsubstituted phosphoric acid residue (wherein a heteroatom groupselected from the group consisting of CO, O, S, SO, SO₂, NR^(a) (R^(a)is hydrogen or lower alkyl), —N═ and ═N— may intervene in the loweralkyl); and

provided that the compounds wherein B¹ is NR²², the broken linerepresents the absence of a bond, and R⁴ is unsubstituted ethyl orunsubstituted isopropyl are excluded.

The compound represented by the following formula (I-3-1), or itspharmaceutically acceptable salt according to the above item [20]:

wherein F ring is substituted or unsubstituted heterocycle;

B¹ is CR²⁰R²¹, N or NR²²;

when B¹ is CR²⁰R²¹, the broken line represents the absence of a bond,and B² is N;

when B¹ is N, the broken line represents the presence of a bond, and B²is C;

when B¹ is NR²², the broken line represents the absence of a bond, andB² is CR²⁰; and

the other symbols are defined as the same above item [20].

[22] The compound or its pharmaceutically acceptable salt according tothe above item [20], wherein F ring is represented by any one of thefollowing rings:

wherein Z¹, Z², Z³, Z⁴ and Z⁵ are each independently CR¹R², CR¹, O, S,SO, SO₂, N or NR¹⁹;

or Z¹ and Z³, Z¹ and Z⁴, Z¹ and Z⁵, Z² and Z⁴, Z² and Z⁵, or Z³ and Z⁵may be taken together to form substituted or unsubstituted (C2-C4)bridge;

R¹ and R² are each independently, hydrogen, halogen, substituted orunsubstituted lower alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkyl lower alkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy,substituted or unsubstituted lower alkenyloxy, substituted orunsubstituted aryl, substituted or unsubstituted aryl lower alkyl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclyl lower alkyl,substituted or unsubstituted heterocyclyloxy, substituted orunsubstituted phosphoric acid residue, aryl substituted with substitutedor unsubstituted phosphoric acid residue, hydroxy substituted withsubstituted or unsubstituted phosphoric acid residue, amino substitutedwith substituted or unsubstituted phosphoric acid residue, lower alkylsubstituted with substituted or unsubstituted phosphoric acid residue(wherein a heteroatom group selected from the group consisting of O, S,SO, SO₂, NR⁵ (wherein R⁵ is defined as the same above item [20]), —N═and ═N— may intervene in the lower alkyl), hydroxy, substituted orunsubstituted amino, substituted or unsubstituted d lower alkylcarbonyl,substituted or unsubstituted cycloalkylcarbonyl, substituted orunsubstituted cycloalkyl lower alkylcarbonyl, substituted orunsubstituted lower alkoxycarbonyl, substituted or unsubstitutedarylcarbonyl, substituted or unsubstituted aryl lower alkylcarbonyl,substituted or unsubstituted aryloxycarbonyl, substituted orunsubstituted heterocyclylcarbonyl, substituted or unsubstitutedheterocyclyl lower alkylcarbonyl, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstituted aminocarbonyl,substituted or unsubstituted ureido or substituted or unsubstitutedthioureido;

or R¹ and R² may be taken together to form oxo, thioxo or substituted orunsubstituted spiro ring;

R¹⁹ is hydrogen, substituted or unsubstituted lower alkyl, loweralkenyl, substituted or unsubstituted lower alkylcarbonyl or substitutedor unsubstituted lower alkylsulfonyl;

the broken line represents the presence or absence of a bond; and

the other symbols are defined as the same above item [20].

The compound or its pharmaceutically acceptable salt according to theabove item [21], wherein F ring is represented by any one of thefollowing rings:

wherein H ring is substituted or unsubstituted carbocycle or substitutedor unsubstituted heterocycle;

Z¹, Z², Z³, Z⁴ and Z⁵ are each independently CR¹R², CR¹, C, O, S, SO,SO₂, N or NR¹⁹ (when Z¹, Z², Z³, Z⁴ or Z⁵ is/are constituent atom(s) ofH ring, Z¹, Z², Z³, Z⁴ and Z⁵ are each independently CR¹, C or N);

or Z¹ and Z³, Z¹ and Z⁴, Z¹ and Z⁵, Z² and Z⁴, Z² and Z⁵, or Z³ and Z⁵may be taken together to form substituted or unsubstituted (C2-C4)bridge;

R¹ and R² are each independently, hydrogen, halogen, substituted orunsubstituted lower alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkyl lower alkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy,substituted or unsubstituted lower alkenyloxy, substituted orunsubstituted aryl, substituted or unsubstituted aryl lower alkyl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclyl lower alkyl,substituted or unsubstituted heterocyclyloxy, substituted orunsubstituted phosphoric acid residue, aryl substituted with substitutedor unsubstituted phosphoric acid residue, hydroxy substituted withsubstituted or unsubstituted phosphoric acid residue, amino substitutedwith substituted or unsubstituted phosphoric acid residue, lower alkylsubstituted with substituted or unsubstituted phosphoric acid residue(wherein a heteroatom group selected from the group consisting of O, S,SO, SO₂, NR⁵ (wherein R⁵ is defined as the same above item [20]), —N═and ═N— may intervene in the lower alkyl), hydroxy, substituted orunsubstituted amino, substituted or unsubstituted lower alkylcarbonyl,substituted or unsubstituted cycloalkylcarbonyl, substituted orunsubstituted cycloalkyl lower alkylcarbonyl, substituted orunsubstituted lower alkoxycarbonyl, substituted or unsubstitutedarylcarbonyl, substituted or unsubstituted aryl lower alkylcarbonyl,substituted or unsubstituted aryloxycarbonyl, substituted orunsubstituted heterocyclylcarbonyl, substituted or unsubstitutedheterocyclyl lower alkylcarbonyl, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstituted aminocarbonyl,substituted or unsubstituted ureido or substituted or unsubstitutedthioureido;

or R¹ and R² may be taken together to form oxo, thioxo or substituted orunsubstituted spiro ring;

R¹⁹ is hydrogen, substituted or unsubstituted lower alkyl, loweralkenyl, substituted or unsubstituted lower alkylcarbonyl or substitutedor unsubstituted lower alkylsulfonyl;

the broken line represents the presence or absence of a bond; and

the other symbols are defined as the same above item [20].

[24] The compound or its pharmaceutically acceptable salt according tothe above item [23], wherein H ring is substituted or unsubstituted 4-to 7-membered carbocycle or substituted or unsubstituted 4- to7-membered heterocycle.[25] The compound represented by the following formula (I-3-2), or itspharmaceutically acceptable salt according to the above item [20]:

wherein G ring is substituted or unsubstituted carbocycle or substitutedor unsubstituted heterocycle;

B¹ is CR²¹ or N;

when B¹ is CR²¹, B² is N; when B¹ is N, B² is CR²¹; and

the other symbols are defined as the same above item [20].

[26] The compound or its pharmaceutically acceptable salt according tothe above item [25], wherein G ring is represented by any one of thefollowing rings:

[27] The compound or its pharmaceutically acceptable salt according toany one of the above items [20] to [26], wherein B² is N or NR²²(wherein R²² is defined as the same above item [20]; proviso when thebroken line represents the presence of a bond or when B² is constituentatom of F ring or G ring, B² is N).[28] The compound represented by the following formula (I-3-3) or(I-3-4), or its pharmaceutically acceptable salt according to any one ofthe above items [20] to [27]:

wherein R¹¹, R^(12a), R^(12b) and R¹³ are each independently, hydrogen,halogen, substituted or unsubstituted lower alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl loweralkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkoxy, substituted or unsubstituted loweralkenyloxy, substituted or unsubstituted aryl, substituted orunsubstituted aryl lower alkyl, substituted or unsubstituted aryloxy,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclyl lower alkyl, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted phosphoric acid residue, aryl substitutedwith substituted or unsubstituted phosphoric acid residue, hydroxysubstituted with substituted or unsubstituted phosphoric acid residue,amino substituted with substituted or unsubstituted phosphoric acidresidue, lower alkyl substituted with substituted or unsubstitutedphosphoric acid residue (wherein a heteroatom group selected from thegroup consisting of O, S, SO, SO₂, NR⁵ (wherein R⁵ is defined as thesame above item [20]), —N═ and ═N— may intervene in the lower alkyl),hydroxy, substituted or unsubstituted amino, substituted orunsubstituted lower alkylcarbonyl, substituted or unsubstitutedcycloalkylcarbonyl, substituted or unsubstituted cycloalkyl loweralkylcarbonyl, substituted or unsubstituted lower alkoxycarbonyl,substituted or unsubstituted arylcarbonyl, substituted or unsubstitutedaryl lower alkylcarbonyl, substituted or unsubstituted aryloxycarbonyl,substituted or unsubstituted heterocyclylcarbonyl, substituted orunsubstituted heterocyclyl lower alkylcarbonyl, substituted orunsubstituted heterocyclyloxycarbonyl, substituted or unsubstitutedaminocarbonyl, substituted or unsubstituted ureido or substituted orunsubstituted thioureido;

or R^(12a) and R^(12b) may be taken together to form oxo, thioxo;

when the compound is represented by formula (I-3-4), R^(12a) and R^(12b)may be taken together to form substituted or unsubstituted spiro ring;and

Q is defined as the same above item [20].

The compound represented by the following formula (I-3-5) or (I-3-6), orits pharmaceutically acceptable salt according to any one of the aboveitems [20] to [22]:

wherein X is CR^(18a)R^(18b), NR²⁴, O or S;

R^(15a), R^(15b), R^(16a), R^(16b), R^(17a), R^(17b), R^(18a), R^(18b)and R²⁴ are each independently, hydrogen, halogen, substituted orunsubstituted lower alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkyl lower alkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy,substituted or unsubstituted lower alkenyloxy, substituted orunsubstituted aryl, substituted or unsubstituted aryl lower alkyl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclyl lower alkyl,substituted or unsubstituted heterocyclyloxy, substituted orunsubstituted phosphoric acid residue, aryl substituted with substitutedor unsubstituted phosphoric acid residue, hydroxy substituted withsubstituted or unsubstituted phosphoric acid residue, amino substitutedwith substituted or unsubstituted phosphoric acid residue, lower alkylsubstituted with substituted or unsubstituted phosphoric acid residue(wherein a heteroatom group selected from the group consisting of O, S,SO, SO₂, NR⁵ (wherein R⁵ is defined as the same above item [20]), —N═and ═N— may intervene in the lower alkyl), hydroxy, substituted orunsubstituted amino, substituted or unsubstituted lower alkylcarbonyl,substituted or unsubstituted cycloalkylcarbonyl, substituted orunsubstituted cycloalkyl lower alkylcarbonyl, substituted orunsubstituted lower alkoxycarbonyl, substituted or unsubstitutedarylcarbonyl, substituted or unsubstituted aryl lower alkylcarbonyl,substituted or unsubstituted aryloxycarbonyl, substituted orunsubstituted heterocyclylcarbonyl, substituted or unsubstitutedheterocyclyl lower alkylcarbonyl, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstituted aminocarbonyl,substituted or unsubstituted ureido or substituted or unsubstitutedthioureido;

or R^(15a) and R^(15b), R^(16a) and R^(16b), R^(17a) and R^(17b), orR^(18a) and R^(18b) may be taken together to form oxo, thioxo orsubstituted or unsubstituted spiro ring;

or R^(15b) and R^(16b), R^(16b) and R^(18b), and/or R^(17b) and R^(18b)may be taken together to form substituted or unsubstituted carbocycle orsubstituted or unsubstituted heterocycle; or R^(15b) and R^(17b),R^(15b) and R^(18b), or R^(16b) and R^(17b) may be taken together toform substituted or unsubstituted (C2-C4) bridge;

or R^(16b) and R²⁴, or R^(17b) and R²⁴ may be taken together to formsubstituted or unsubstituted heterocycle; or R^(15b) and R²⁴ may betaken together to form substituted or unsubstituted (C2-C4) bridge; and

the other symbols are defined as the same above item [20].

[30] The compound or its pharmaceutically acceptable salt according tothe above item [29], wherein R^(15a) is hydrogen or substituted orunsubstituted lower alkyl.[31] The compound or its pharmaceutically acceptable salt according tothe above item [29] or [30], wherein R^(15b) is hydrogen.[32] The compound or its pharmaceutically acceptable salt according toany one of the above items [29] to [31], wherein R^(16a) is hydrogen orsubstituted or unsubstituted lower alkyl.[33] The compound or its pharmaceutically acceptable salt according toany one of the above items [29] to [32], wherein R^(16b) is hydrogen.[34] The compound or its pharmaceutically acceptable salt according toany one of the above items [29] to [33], wherein R^(17a) is hydrogen orsubstituted or unsubstituted lower alkyl.[35] The compound or its pharmaceutically acceptable salt according toany one of the above items [29] to [34], wherein R^(17b) is hydrogen.[36] The compound or its pharmaceutically acceptable salt according toany one of the above items [29] to [35], wherein R^(18a) is hydrogen orsubstituted or unsubstituted lower alkyl.[37] The compound or its pharmaceutically acceptable salt according toany one of the above items [29] to [36], wherein R^(18b) is hydrogen.[38] The compound or its pharmaceutically acceptable salt according toany one of the above items [29] to [37], wherein R²⁴ is hydrogen orsubstituted or unsubstituted lower alkyl.[39] The compound represented by any one of the following formula, orits pharmaceutically acceptable salt according to the above item [20]:

wherein each Q is defined as the same above item [20].[40] The compound or its pharmaceutically acceptable salt according toany one of the above items [1] to [39], wherein Q is substituted orunsubstituted heterocyclyl.[41] The compound or its pharmaceutically acceptable salt according toany one of the above items [1] to [40], wherein Q is substituted orunsubstituted 5- to 7-membered monocyclic heterocyclyl.[42] The compound or its pharmaceutically acceptable salt according toany one of the above items [1] to [41], wherein Q is represented by anyone of the following formula:

[43] The compound or its pharmaceutically acceptable salt according toany one of the above items [1] to [42], wherein Q is carbocyclyl orheterocyclyl substituted with the same or different, 1 to 4substituent(s) selected from Substituent group A.Substituent group A: lower alkyl, lower alkoxy, halogen, halogenatedlower alkyl, halogenated lower alkoxy, and the group of formula (B):

wherein X^(A) is a group selected from the following group:X^(A1): a single bond;X^(A2): a group selected from C(═O) and C(═S);X^(A3): a heteroatom group selected from O, S, SO, SO₂, and N(R^(1′))wherein R^(1′) is hydrogen or lower alkyl;X^(A4): a group formed by linking the same or different, two or moregroups selected from X^(A2) and X^(A3);X^(A5): a group selected from —N═N—, —C(R^(1′))═N—, or —N═C(R^(1′))—wherein R^(1′) is hydrogen or lower alkyl;X^(A6): substituted or unsubstituted lower alkylene or substituted orunsubstituted lower alkenylene;X^(A7): X^(A6) intervened by one or any two or more groups selected fromX^(A2), X^(A3), X^(A4), and X^(A5);X^(A8): a group CR^(1′)R^(2′) wherein R^(1′) and R^(2′) are takentogether with neighboring atoms to form carbocycle or heterocycle; andX^(A9): a spacer consisting of any combination of X^(A1) to X^(A8);

R is a group independently selected from the following group:

(1) lower alkyl,(2) lower alkoxy,(3) halogen,(4) halogenated lower alkyl,(5) halogenated lower alkoxy, and(6) lower cycloalkyl.m is an integer of 0 to 5.[44] The compound or its pharmaceutically acceptable salt according toany one of the above items [1] to [43], wherein Q is represented by thefollowing formula (1) or (2):

wherein each symbol is defined as the same above item [43].[45] The compound or its pharmaceutically acceptable salt according tothe above item [43] or [44], wherein X^(A) is lower alkylene; R isindependently lower alkoxy, halogen or halogenated lower alkyl; and m is1 or 2.[46] The compound or its pharmaceutically acceptable salt according toany one of the above items [1] to [45], wherein Q is substituted orunsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl

provided that the following compounds are excluded:

[47] The compound or its pharmaceutically acceptable salt according toany one of the above items [1] to [46], wherein Q is represented by anyone of the following groups:

[48] The compound represented by any one of the following formula(I-1′), (I-2′) or (I-3′), or its pharmaceutically acceptable salt:

wherein Y is represented by any one of the following group:

wherein R^(Y) is substituted or unsubstituted alkyl; andthe other symbols are defined as the same above item [1].[49] A pharmaceutical composition comprising the compound according toany of the above items [1] to [48], or a pharmaceutically acceptablesalt thereof.[50] The pharmaceutical composition according to the above item [49],which has anti-HIV activity.[51] The pharmaceutical composition according to the above [49], whichhas an HIV integrase inhibitory activity.[52] A method for treating or preventing AIDS by administering thecompound of any one of the above items [1] to [48] to human or animals,or a pharmaceutically acceptable salt thereof.[53] The compound of any one of the above items [1] to [48], or apharmaceutically acceptable salt thereof for medical treatment.[54] Use of the compound of any one of the above items [1] to [48], orits pharmaceutically acceptable salt for the manufacture of atherapeutic or preventive agent for AIDS.[55] The compound or its pharmaceutically acceptable salt according tothe above item [1],provided that the compounds having combination of S-T-U are excludedwherein S is represented by any group of the following:

T is represented by any group of the following:

wherein the left bond is combined to S, and the right bond is combinedto U;

U is represented by any group of the following:

[56] The compound or its pharmaceutically acceptable salt according toany one of the above item [20] or [26], wherein B¹ and B² are eachindependently CR²⁰R²¹ or CR²³.

The present invention further provides a method of preventing ortreating HIV that is characterized by administering an effective amountof the above-described compound to a human.

The present invention further provides the above-described compound forusing as an anti-HIV agent.

Effect of the Invention

The present compound has integrase inhibitory activity and/or cellproliferation inhibitory activity against viruses, in particular, HIVand drug-resistant strains thereof. Thus, the compound is useful inpreventing or treating various diseases, viral infections (e.g., AIDS),and the like in which integrase participates. More preferably, thepresent compound is also excellent in resistance profile that it isdifficult for the compound to cause a new HIV-resistant virus, and thelike. Further preferably, the present compound has a preventive ortherapeutic effect on HIV drug-resistant virus. Further more preferably,the present compound is useful as a pharmaceutical agent that isexcellent in solubility, peroral absorbability, metabolic stability,bioavailability or the like, and for which there is little concern aboutcytotoxicity and a side effect (e.g., mutagenicity, the QT intervalprolongation of the electrocardiogram).

MODE FOR CARRYING OUT THE INVENTION

The terms used herein are explained below. Each term, alone or incombination with another term, means as follows.

“Lower alkylene” means a linear or branched C₁₋₆ lower alkylene such asmethylene, ethylene, trimethylene, propylene, tetramethylene,ethylethylene, pentamethylene, hexamethylene, or the like. Preferred isa C₁₋₄ linear lower alkylene such as methylene, ethylene, trimethylene,or tetramethylene. More preferred is methylene or ethylene.

“Lower alkenylene” means a linear or branched C₂₋₆ lower alkenylenegroup, which consists of the above “Lower alkylene” having one or moredouble bonds, such as vinylene, propylene, or butenylene. Preferred is aC₂₋₃ linear lower alkenylene such as vinylene or propylene.

“Alkyl” means a linear or branched C₁₋₁₀ alkyl group such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl,n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. Preferred is a C₁₋₆lower alkyl and more preferred is a C₁₋₄ lower alkyl, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, and isohexyl.

When lower alkyl is intervened by —N═ or ═N—, the lower alkyl may have adouble bond to form, for example, —CH₂—N═CH₂, —CH═N—CH₃, or the like.

“Alkenyl” means a linear or branched C₂₋₈ alkenyl, which consists of theabove “alkyl” having one or more double bonds, such as vinyl,1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl,3-methyl-2-butenyl, and the like. Preferred is C₂₋₆ lower alkenyl, andmore preferred is C₂₋₄ lower alkenyl.

“Lower alkenyloxy” means an oxy attached to the above “lower alkenyl”,such as vinyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy,2-butenyloxy, 3-butenyloxy, 1, 3-butadienyloxy, 3-methyl-2-butenyloxy,and the like.

“Alkynyl” means a linear or branched C₂₋₈ alkenyl, which consists of theabove “alkyl” having one or more triple bonds, such as ethynyl,propargyl, and the like. Preferred is C₂₋₆ lower alkynyl, and morepreferred is C₂₋₄ lower alkynyl.

“Carbocyclic group” means a saturated or unsaturated C₃₋₁₀ carbocyclicgroup, and includes cycloalkyl, cycloalkenyl, and aryl.

“Cycloalkyl” means a C₃₋₁₀ cyclic saturated hydrocarbon group, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl,cyclooctyl, and the like. Preferred is C₃₋₆ cycloalkyl.

“Cycloalkyl lower alkyl” means a lower alkyl substituted with the abovecycloalkyl, such as cyclopropylmethyl, cyclopropylethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl,and the like. Preferred is C₃₋₆ cycloalkyl lower alkyl.

“Aryl” means a monocyclic aromatic hydrocarbon group (phenyl) and apolycyclic aromatic hydrocarbon (e.g., 1-naphthyl, 2-naphthyl,1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl,3-phenanthryl, 4-phenanthryl, 9-phenanthryl, and the like). Preferred isphenyl or naphthyl (e.g., 1-napthyl, 2-naphthyl).

“Aralkyl” or “aryl lower alkyl” means the above “lower alkyl”substituted with one to three of the above “aryl”, such as benzyl,diphenylmethyl, triphenylmethyl, phenethyl, 1-napthylmethyl,2-napthylmethyl, and the like. Preferred is benzyl.

“Aryloxy” means an oxy attached to the above “aryl”, such as1-naphthyloxy, 2-naphthyloxy, 1-anthryloxy, 2-anthryloxy, 9-anthryloxy,1-phenanthryloxy, 2-phenanthryloxy, 3-phenanthryloxy, 4-phenanthryloxy,9-phenanthryloxy, and the like. Preferred is phenyloxy or naphthyloxy(e.g., 1-napthyloxy, 2-naphthyloxy).

“Heterocyclic group” means “heteroring” or “heteroaryl”.

“Heteroring” means a non-aromatic heterocyclic group (preferably 5- to7-membered ring) which has at least one of nitrogen, oxygen, phosphorusand/or sulfur atoms in the ring and may be bonded at any substitutableposition such as 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl,1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl,2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl,4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl,1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino,2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperadinyl, 2-piperadinyl,2-morpholinyl, 3-morpholinyl, morpholino, tetrahydropyranyl, and thelike. The “non-aromatic heterocyclic group” is a saturated orunsaturated ring.

“Heteroaryl” means a monocyclic aromatic heterocyclic group or acondensed aromatic heterocyclic group.

Monocyclic aromatic heterocyclic group means a group derived from a 5-to 8-membered aromatic ring optionally containing one to four of oxygen,sulfur, phosphorus and/or nitrogen atoms in the ring wherein the groupmay be bonded at any substitutable position.

Condensed aromatic heterocyclic group means a group wherein a 5- to8-membered aromatic ring optionally containing one to four of oxygen,sulfur, phosphorus and/or nitrogen atoms in the ring is condensed withone to four of 5- to 8-membered aromatic carbocycle(s) or the other 5-to 8-membered aromatic heterocycle(s), and wherein the group may bebonded at any substitutable position.

Examples of “heteroaryl” include furyl (e.g., 2-furyl, 3-furyl), thienyl(e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl,4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl),triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl,1,2,4-triazol-4-yl), tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl,5-tetrazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl),isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl(e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl,isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl),pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g.,3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl), furazanyl (e.g., 3-furazanyl), pyrazinyl(e.g., 2-pyrazinyl), oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl),benzofuryl (e.g., 2-benzo[b]furyl, 3-benzo[b]furyl, 4-benzo[b]furyl,5-benzo[b]furyl, 6-benzo[b]furyl, 7-benzo[b]furyl), benzothienyl (e.g.,2-benzo[b]thienyl, 3-benzo[b]thienyl, 4-benzo[b]thienyl,5-benzo[b]thienyl, 6-benzo[b]thienyl, 7-benzo[b]thienyl), benzimidazolyl(e.g., 1-benzoimidazolyl, 2-benzoimidazolyl, 4-benzoimidazolyl,5-benzoimidazolyl), dibenzofuryl, benzoxazolyl, quinoxalinyl (e.g.,2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl), cinnolinyl (e.g.,3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl,8-cinnolinyl), quinazolinyl (e.g., 2-quinazolinyl, 4-quinazolinyl,5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl),quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl,6-quinolyl, 7-quinolyl, 8-quinolyl), phthalazinyl (e.g., 1-phthalazinyl,5-phthalazinyl, 6-phthalazinyl), isoquinolyl (e.g., 1-isoquinolyl,3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl,7-isoquinolyl, 8-isoquinolyl), purinyl, pteridinyl (e.g., 2-pteridinyl,4-pteridinyl, 6-pteridinyl, 7-pteridinyl), carbazolyl, phenanthridinyl,acridinyl (e.g., 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl,9-acridinyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl,5-indolyl, 6-indolyl, 7-indolyl), isoindolyl, phenazinyl (e.g.,1-phenazinyl, 2-phenazinyl), phenothiazinyl (e.g., 1-phenothiazinyl,2-phenothiazinyl, 3-phenothiazinyl, 4-phenothiazinyl), or the like.

“Heterocycle” and “heterocyclic ring” mean a ring from which the aboveheterocyclic group can be derived.

“Spiro cycle” means a ring constituted two rings sharing a carbon atom.Two tings may be each independently carbocycle or heterocycle.

“Heterocyclic lower alkyl” and “heterocyclyl lower alkyl” mean loweralkyl substituted with the above “heterocyclic group”.

“Heterocyclyloxy” means an oxy attached to the above “heterocyclicgroup”.

“Lower alkoxy” or “alkoxy” mean an oxy attached to the above “loweralkyl” or “alkoxy”, such as methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, tert-butoxy, and the like.

“Lower alkylcarbonyl”, “cycloalkylcarbonyl”, “cycloalkyl loweralkylcarbonyl”, “lower alkoxycarbonyl”, “arylcarbonyl”, “aryl loweralkylcarbonyl”, “aryloxycarbonyl”, “heterocyclylcarbonyl”, “heterocyclyllower alkylcarbonyl”, and “heterocyclyloxycarbonyl” means a carbonylattached to the above “lower alkyl”, “cycloalkyl”, “cycloalkyl loweralkyl”, “lower alkoxy”, “aryl”, “aryl lower alkyl”, “aryloxy”,“heterocyclic group”, and “heterocyclyl lower alkyl”, respectively.

“Lower alkylsulfonyl” means the alkyl part of a lower alkylsulfonyl isthe above “lower alkyl”, such as methylsulfonyl, and the like.

When a substituent(s) is/are present on “substituted or unsubstitutedlower alkyl”, “substituted or unsubstituted cycloalkyl”, “substituted orunsubstituted cycloalkyl lower alkyl”, “substituted or unsubstitutedlower alkenyl”, “substituted or unsubstituted lower alkynyl”,“substituted or unsubstituted lower alkoxy”, “substituted orunsubstituted aryl”, “substituted or unsubstituted aryl lower alkyl”,“substituted or unsubstituted aryloxy”, “substituted or unsubstitutedheterocycle”, “substituted or unsubstituted heterocyclic group”,“substituted or unsubstituted heterocyclyl lower alkyl”, “substituted orunsubstituted heterocyclyloxy”, “substituted or unsubstituted loweralkenyloxy”, “substituted or unsubstituted lower alkylcarbonyl”,“substituted or unsubstituted cycloalkylcarbonyl”, “substituted orunsubstituted cycloalkyl lower alkylcarbonyl”, “substituted orunsubstituted lower alkoxycarbonyl”, “substituted or unsubstitutedarylcarbonyl”, “substituted or unsubstituted aryl lower alkylcarbonyl”,“substituted or unsubstituted aryloxycarbonyl”, “substituted orunsubstituted heterocyclylcarbonyl”, “substituted or unsubstitutedheterocyclyl lower alkylcarbonyl”, “substituted or unsubstitutedheterocyclyloxycarbonyl”, “substituted or unsubstituted lower alkylene”,“substituted or unsubstituted lower alkenylene”, “substituted orunsubstituted phosphoric acid residue”, “substituted or unsubstitutedcarbocycle”, “substituted or unsubstituted lower alkylsulfonyl”,“substituted or unsubstituted spiroring”, “substituted or unsubstituted(C2-C4)bridge” or the like, each may be substituted with the same ordifferent, 1 to 4 group(s) selected from Substituent group B andSubstituent group A (described below) at any position.

Examples of Substituent group B include hydroxy, carboxy, halogen (F,Cl, Br, I), halo lower alkyl (e.g., CF₃, CH₂CF₃, CH₂CCl₃), halo loweralkoxy (e.g., OCF₃, OCH₂CF₃, OCH₂CCl₃), lower alkyl (e.g., methyl,ethyl, isopropyl, tert-butyl), lower alkenyl (e.g., vinyl), loweralkynyl (e.g., ethynyl), cycloalkyl (e.g., cyclopropyl), cycloalkenyl(e.g., cyclopropenyl), lower alkoxy (e.g., methoxy, ethoxy, propoxy,butoxy), lower alkenyloxy (e.g., vinyloxy, allyloxy), loweralkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl), nitro, nitroso, substituted or unsubstituted amino(e.g., alkylamino (e.g., methylamino, ethylamino, dimethylamino),acylamino (e.g., acetylamino, benzoylamino), aralkylamino (e.g.,benzylamino, tritylamino), hydroxyamino)), azido, aryl (e.g., phenyl),aralkyl (e.g., benzyl), cyano, isocyano, isocyanato, thiocyanato,isothiocyanato, mercapto, alkylthio (e.g., methylthio), alkylsulfonyl(e.g., methanesulfonyl, ethanesulfonyl), substituted or unsubstitutedalkylsulfonylamino (e.g., methanesulfonylamino, ethanesulfonylamino,N-methylsulfonyl-N′-methylamino), substituted or unsubstituted carbamoyl(e.g., alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl)), sulfamoyl, acyl (e.g., formyl, acetyl), formyloxy,haloformyl, oxalo, thioformyl, thiocarboxy, dithiocarboxy,thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazino, azido, ureido,amidino, guanidino, phthalimido, oxo, phosphoric acid residue,phosphoric-acid-residue-substituted lower alkyl (which may be having aheteroatom group(s)), aryl substituted with a phosphoric acid residue,aralkyl substituted with a phosphoric acid residue, hydroxy lower alkyland the like, more preferably hydroxy, carboxy, halogen (F, Cl, Br, I),halo lower alkyl (e.g., CF₃, CH₂CF₃, CH₂CCl₃), halo lower alkoxy (e.g.,OCF₃, OCH₂CF₃, OCH₂CCl₃), lower alkyl (e.g., methyl, ethyl, isopropyl,tert-butyl), lower alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy),substituted or unsubstituted amino (e.g., alkylamino (e.g., methylamino,ethylamino, dimethylamino), oxo, phosphoric acid residue, and the like.

Examples of a substituent(s) of “substituted or unsubstituted amino”,“substituted or unsubstituted carbamoyl”, “substituted or unsubstitutedaminocarbonyl”, “substituted or unsubstituted ureido” or “substituted orunsubstituted thioureido” include mono- or di-lower alkyl, loweralkylcarbonyl, or lower alkylsulfonyl, substituted or unsubstitutedlower alkyl (e.g., methyl, ethyl, isopropyl, benzyl, carbamoylalkyl(e.g., carbamoylmethyl), mono- or di-lower alkylcarbamoyl lower alkyl(e.g., dimethylcarbamoylethyl), hydroxy lower alkyl, heterocyclyl loweralkyl (e.g., morpholinoethyl, tetrahydropyranylethyl), alkoxycarbonyllower alkyl (e.g., ethoxycarbonylmethyl, ethoxycarbonylethyl), mono- ordi-lower alkylamino lower alkyl (e.g., dimethylaminoethyl)), loweralkoxy lower alkyl (e.g., methoxyethyl, ethoxymethyl, ethoxyethyl,isopropoxyethyl, and the like), acyl (e.g., formyl, substituted orunsubstituted lower alkylcarbonyl (e.g., acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl,methoxyethylcarbonyl, 2,2,2-trifluoroethylcarbonyl,ethoxycarbonylmethylcarbonyl), lower alkoxy lower alkylcarbonyl (e.g.,methoxyethylcarbonyl), lower alkylcarbamoyl lower alkylcarbonyl (e.g.,methylcarbamoylethylcarbonyl), alkoxycarbonylacetyl), substituted orunsubstituted arylcarbonyl (e.g., benzoyl, toluoyl), substituted orunsubstituted aralkyl (e.g., benzyl, 4-fluorobenzyl), hydroxy,substituted or unsubstituted lower alkylsulfonyl (e.g., methanesulfonyl,ethanesulfonyl, isopropylsulfonyl, 2,2,2-trifluoroethanesulfonyl,benzylsulfonyl, methoxyethylsulfonyl), arylsulfonyl substituted orunsubstituted with lower alkyl or halogen (e.g., benzenesulfonyl,toluenesulfonyl, 4-fluorobenzenesulfonyl), cycloalkyl (e.g.,cyclopropyl), aryl substituted or unsubstituted with lower alkyl (e.g.,phenyl, trityl), lower alkylaminosulfonyl (e.g., methylaminosulfonyl,dimethylaminosulfonyl), lower alkylaminocarbonyl (e.g.,dimethylaminocarbonyl), lower alkoxycarbonyl (e.g., ethoxycarbonyl),cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, cyclohexylcarbonyl),substituted or unsubstituted sulfamoyl (e.g., sulfamoyl,methylsulfamoyl, dimethylsulfamoyl), lower alkylcarbonylamino (e.g.,methylcarbonylamino), heterocycle (e.g., morpholino, tetrahydropyranyl),substituted or unsubstituted amino (e.g., mono- or di-alkylamino (e.g.,dimethylamino), formylamino), and the like.

As to an amino group of “substituted or unsubstituted amino”,“substituted or unsubstituted aminocarbonyl”, or “substituted orunsubstituted carbamoyl”, two substituents on the amino group togetherwith the adjacent nitrogen atom may form a nitrogen-containingheterocycle which may contains sulfur and/or oxygen atoms in the ring(preferably 5- to 7-membered ring, also preferably saturated ring) andthe ring is substituted or unsubstituted with oxo or hydroxy. A 5- or6-membered ring and the like such as piperazinyl, piperidino,morpholino, pyrrolidino, 2-oxopiperidino, 2-oxopyrrolidino,4-hydroxymorpholino and the like are preferred.

“Phosphoric acid residue” means a group represented by the formula:—PO(OH)₂. “Substituted or unsubstituted phosphoric acid residue” means aphosphoric acid residue in which the OH part and/or hydrogen of the OHmay be substituted.

More Preferred Embodiments

Q is a carbocyclic group that is optionally substituted and optionallycondensed or a heterocyclic group that is optionally substituted andoptionally condensed.

Q is preferably a substituted or unsubstituted heterocyclic group.

Q is more preferably a 5- to 7-membered monocyclic heterocyclic groupthat is optionally substituted and contains one to four heteroatoms thatare one or the same or different, two or more heteroatoms selected fromO, S, and N atoms. Q is, further preferably, a monocyclic aromaticheterocyclic group containing one to three of the heteroatoms,particularly preferably, a 5-membered ring, and most preferably, a5-membered monocyclic aromatic heterocyclic group containing one S atomand one or two N atoms. Preferred Q is, specifically, a ring shownbelow:

Q is, more preferably, a ring of the above-described (1), (2), (3), (5),(6), (7), (10), (11), (12), (13), (14), (15), (16), or (17) particularlypreferably a ring of the above-described (1), (2), (3), (5), or (17) andmost preferably a ring of the above-described (1), (2), or (17).

Examples of a condensed ring of the above-described monocyclicheterocyclic group include a benzene ring and other monocyclicheterocycle (preferably 5- to 7-membered).

Q is more preferably a carbocyclyl or heterocyclyl substituted with thesame or different, one to four, further preferably one or two,substituent(s) selected from Substituent group A.

Substituent group A: lower alkyl (e.g., methyl, ethyl), lower alkoxy(e.g., methoxy, ethoxy), halogen (e.g., F, Br), halogenated lower alkyl(e.g., —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃), halogenatedlower alkoxy (e.g., —OCH₂F, —OCHF₂, —OCF₃, —OCH₂CH₂F, —OCH₂CHF₂,—OCH₂CF₃), and a group represented by the formula:

in the above formula,X^(A) is a group selected from the following group:X^(A1): a single bond;X^(A2): a group selected from C(═O) and C(═S);X^(A3): a heteroatom group selected from O, S, SO, SO₂, and N(R^(1′))wherein R^(1′) is hydrogen or lower alkyl;X^(A4): a group formed by linking the same or different, two or moregroups selected from X^(A2) and X^(A3) (e.g., —CONH—, —CONHNH—,—CONHNHCO—, —CONHO—, —CONHNHSONH—, —CONHNMe-, —NHCONH—, —NHCOO—);X^(A5): a group selected from —N═N—, —C(R^(1′))═N—, or —N═C(R^(1′))—wherein R^(1′) is hydrogen or lower alkyl;X^(A6): substituted or unsubstituted lower alkylene or substituted orunsubstituted lower alkenylene (example of substituent: methyl, phenyl);

-   -   X^(A7): X^(A6) intervened by one or any two or more groups        selected from X^(A2), X^(A3), X^(A4), and    -   X^(A5) (e.g., —CONHCH₂—, —CONMeCH₂—, —CONHCH₂CH₂O—,        —CONHCH₂CH₂—SO₂—, —CONHCH₂CH₂CH₂—);        X^(A8): a group CR^(1′)R^(2′) wherein R^(1′) and R^(2′) are        taken together with neighboring atoms to form carbocycle (e.g.,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) or heterocycle        (e.g., oxetane, oxolane); and        X^(A9): a spacer consisting of any combination of X^(A1) to        X^(A7).

In X^(A), “intervene” may be any of cases where one or any two or moregroups selected from X^(A2), X^(A3), X^(A4), and X^(A5) 1) are presentbetween carbon atoms constituting lower alkylene or lower alkenylene, 2)are present at an end of lower alkylene or lower alkenylene, andwhere 1) and 2) coexist.

X^(A) is a spacer consisting of, preferably, one to five atoms linked,and more preferably, one to three atoms linked. X^(A) is more preferablylower alkylene, and further preferably C1-C3 alkylene.

R is a group independently selected from the following group:

(1) lower alkyl,(2) lower alkoxy,(3) halogen,(4) halogenated lower alkyl,(5) halogenated lower alkoxy, and(6) lower cycloalkyl.

R is preferably, independently lower alkoxy, halogen, or halogenatedlower alkyl, and more preferably halogen.

m is an integer of 0 to 5, preferably, 1 or 2.

Q is more preferably substituted with a group shown in theabove-described (B).

Q is, more preferably, a ring of the above-described (Q1) to (Q30).Particularly preferable Q is (Q1), (Q2), (Q15), (Q21), (Q23), (Q24) or(Q25).

R³ may be a variety of substituents as far as they do not adverselyaffect on the pharmacological activity of the present compound. Examplesthereof include, for example, hydrogen, halogen, hydroxy, substituted orunsubstituted lower alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedlower alkoxy, substituted or unsubstituted lower alkenyloxy, substitutedor unsubstituted aryl, substituted or unsubstituted aryloxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclyloxy or substituted or unsubstituted amino, and the like.Examples of a substituent(s) in the “substituted or unsubstituted” on R³include halogen, hydroxy, amino, lower alkylamino, cyano, carboxy,formyl, oxo, lower alkyl, lower alkoxy, lower alkylthio, carbamoyl,lower alkylcarbamoyl, aryl, heterocyclyl, lower alkylcarbonyl, loweralkylcarbonyloxy, lower alkoxycarbonyl, halogenated lower alkyl,halogenated lower alkoxy, and the like. More preferred are halogen,hydroxy, amino, lower alkylamino, lower alkyl, lower alkoxy, and thelike.

R³ is more preferably, hydrogen, halogen, hydroxy, lower alkyl, loweralkenyl, lower alkoxy, lower alkenyloxy or amino, further preferably,hydrogen or lower alkyl (e.g., methyl), and particularly preferably,hydrogen.

The broken line represents the presence or absence of a bond.

When the broken line adjacent to the carbon atom connected with R^(x)represents the presence of a bond, R^(x) is absence.

When the broken line adjacent to the carbon atom connected with R⁸represents the presence of a bond, R⁸ is absence.

Both the broken lines adjacent to the carbon atom connected with R⁸cannot represent the presence of a bond at the same time.

The A ring is a substituted or unsubstituted heterocycle containing atleast one N atom. The substituent on the A ring may be selected from theSubstituent group S2, and preferably, the substituent on the A ring islower alkyl. The heterocycle is preferably a 5- to 7-membered ringcontaining one to three, preferably two or three, O, S and/or N atoms,and more preferably is selected from the foregoing heterocycles. The Aring is preferably a ring of (a), (b) or (c), more preferably a ring of(a) or (b), and particularly preferably a ring of (b).

Z¹ is preferably, CR¹R², O, S or NR¹⁹, and more preferably is CR¹R².

Z² is preferably, CR¹R², O, S or NR¹⁹, and more preferably is CR¹R².

Z³ is preferably, CR¹R², O, S or NR¹⁹, and more preferably is CR¹R² orO.

Z⁴ is preferably, CR¹R², O, S or NR¹⁹, and more preferably is CR¹R², Oor NR¹⁹, and particularly preferably is CR¹R² or O.

Z⁵ is preferably, CR¹R², O, S or NR¹⁹, and more preferably is CR¹R² orO.

Z¹ and Z³, Z¹ and Z⁴, Z¹ and Z⁵, Z² and Z⁴, Z² and Z⁵, or Z³ and Z⁵ maybe taken together to form substituted or unsubstituted (C2-C4) bridge(example of substituent: lower alkyl, hydroxy, halogen).

R¹ and R² may be a variety of substituents as far as they do notadversely affect on the pharmacological activity of the presentcompound. Examples thereof include, for example, each independently,hydrogen, halogen, substituted or unsubstituted lower alkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyllower alkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkoxy, substituted or unsubstituted loweralkenyloxy, substituted or unsubstituted aryl, substituted orunsubstituted aryl lower alkyl, substituted or unsubstituted aryloxy,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclyl lower alkyl, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted phosphoric acid residue, aryl substitutedwith substituted or unsubstituted phosphoric acid residue, hydroxysubstituted with substituted or unsubstituted phosphoric acid residue,amino substituted with substituted or unsubstituted phosphoric acidresidue or lower alkyl substituted with substituted or unsubstitutedphosphoric acid residue (A heteroatom group selected from the groupconsisting of O, S, SO, SO₂, NR⁵ (R⁵ is selected independently from thesame substituents group as R⁴), —N═ and ═N— may intervene in the loweralkyl), hydroxy, substituted or unsubstituted amino, substituted orunsubstituted lower alkylcarbonyl, substituted or unsubstitutedcycloalkylcarbonyl, substituted or unsubstituted cycloalkyl loweralkylcarbonyl, substituted or unsubstituted lower alkoxycarbonyl,substituted or unsubstituted arylcarbonyl, substituted or unsubstitutedaryl lower alkylcarbonyl, substituted or unsubstituted aryloxycarbonyl,substituted or unsubstituted heterocyclylcarbonyl, substituted orunsubstituted heterocyclyl lower alkylcarbonyl, substituted orunsubstituted heterocyclyloxycarbonyl, substituted or unsubstitutedaminocarbonyl, substituted or unsubstituted ureido or substituted orunsubstituted thioureido, preferably, hydrogen, halogen, hydroxy,substituted or unsubstituted lower alkyl, substituted or unsubstitutedcycloalkyl, and the like.

Examples of a substituent(s) in the “substituted or unsubstituted” on R¹and R² include halogen, hydroxy, amino, lower alkylamino, cyano,carboxy, formyl, oxo, lower alkyl, lower alkoxy, lower alkylthio,carbamoyl, lower alkylcarbamoyl, aryl, heterocyclyl, loweralkylcarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyl, halogenatedlower alkyl, halogenated lower alkoxy, and the like, more preferably,halogen, hydroxy, amino, lower alkylamino, lower alkyl, lower alkoxy,and the like. R¹ and R² are, more preferably, each independently,hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy,lower alkenyloxy or substituted or unsubstituted amino, furtherpreferably, each independently, hydrogen or lower alkyl (e.g., methyl),particularly preferably, hydrogen.

R¹ and R² may be taken together to form oxo, thioxo or substituted orunsubstituted spiro ring (example of substituent: lower alkyl, halogen,halogenated lower alkyl, hydroxy, amino), preferably, oxo orunsubstituted spiro ring.

R¹⁹ is preferably, 1) hydrogen, 2) substituted or unsubstituted loweralkyl (example of substituent: amino substituted or unsubstituted withmono- or di-lower alkyl, cycloalkyl, hydroxy, an substituted orunsubstituted heterocyclic group (wherein the heterocycle is preferablya 5- to 7-membered ring; example: furyl, thienyl, thiazolyl, pyridyl,morpholino, imidazole; example of substituent: lower alkyl, halogen),substituted or unsubstituted heterocyclylcarbonyl (wherein theheterocycle is preferably a 5- to 7-membered ring; example:morpholinocarbonyl), substituted or unsubstituted phenyl (substituent:lower alkyl, amino, lower alkylamino, hydroxy, halogen, halogenatedlower alkyl, lower alkoxy, halogenated lower alkoxy, lower alkylthio,lower alkylsulfonyl), acetylamino, carbamoyl, mono- or di-loweralkyl-substituted carbamoyl, lower alkylsulfonylamino, lower alkoxy,carbonyl, halogen, thiol, lower alkylthio), 3) lower alkenyl, 4) acyl(e.g., lower alkylcarbonyl), or 5) lower alkylsulfonyl. R¹⁹ may beselected from the Substituent group S2 described below.

Further, A ring may have E ring as the following. In this case, Z¹, Z²,Z³, Z⁴ and Z⁵ constituting E ring are each independently, CR¹, C or N.

A ring is more preferably, the ring of (a) or (b), particularlypreferably, the ring of (B).

E ring is preferably, substituted or unsubstituted 4- to 7-memberedcarbocycle (example of substituent: lower alkyl, halogen, hydroxy,halogenated lower alkyl) or substituted or unsubstituted 4- to7-membered heterocycle (example of substituent: lower alkyl, halogen,hydroxy, halogenated lower alkyl), more preferably, 5- to 6-memberedunsubstituted carbocycle or 5- to 6-membered unsubstituted heterocycle,particularly preferably, 5-membered unsubstituted carbocycle or5-membered unsubstituted heterocycle.

Substituent group S2: hydrogen, halogen, substituted or unsubstitutedlower alkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkyl lower alkyl, substituted or unsubstituted loweralkenyl, substituted or unsubstituted lower alkoxy, substituted orunsubstituted lower alkenyloxy, substituted or unsubstituted aryl,substituted or unsubstituted aryl lower alkyl, substituted orunsubstituted aryloxy, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclyl lower alkyl, substituted orunsubstituted heterocyclyloxy, hydroxy, substituted or unsubstitutedamino, substituted or unsubstituted lower alkylcarbonyl, substituted orunsubstituted cycloalkylcarbonyl, substituted or unsubstitutedcycloalkyl lower alkylcarbonyl, substituted or unsubstituted loweralkoxycarbonyl, substituted or unsubstituted arylcarbonyl, substitutedor unsubstituted aryl lower alkylcarbonyl, substituted or unsubstitutedaryloxycarbonyl, substituted or unsubstituted heterocyclylcarbonyl,substituted or unsubstituted heterocyclyl lower alkylcarbonyl,substituted or unsubstituted heterocyclyloxycarbonyl, substituted orunsubstituted aminocarbonyl, substituted or unsubstituted phosphoricacid residue, aryl substituted with substituted or unsubstitutedphosphoric acid residue, aralkyl substituted with substituted orunsubstituted phosphoric acid residue, hydroxy substituted withsubstituted or unsubstituted phosphoric acid residue, amino substitutedwith substituted or unsubstituted phosphoric acid residue, or loweralkyl substituted with substituted or unsubstituted phosphoric acidresidue (A heteroatom group selected from the group consisting of CO, O,S, SO, SO₂, NR⁵ (R⁵ is selected independently from the same substituentsgroup as R⁴), —N═ and ═N— may intervene in the lower alkyl).

The compound of formula (I-1) is preferably compound represented by thefollowing formula (I-1-1) or (I-2-1), particularly preferably compoundrepresented by formula (I-2-1).

X is CR^(9a)R^(9b) NR¹⁰, O or S, preferably, CR^(9a)R^(9b), NR¹⁰ or O,particularly preferably, CR^(9a)R^(9b) or O.

R^(5a), R^(5b), R^(6a), R^(6b), R^(7a), R^(7b), R⁸, R^(9a), R^(9b) andR¹⁹ may be a variety of substituents as far as they do not adverselyaffect on the pharmacological activity of the present compound. Examplesthereof include, for example, each independently, hydrogen, halogen,substituted or unsubstituted lower alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkyl lower alkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedlower alkoxy, substituted or unsubstituted lower alkenyloxy, substitutedor unsubstituted aryl, substituted or unsubstituted aryl lower alkyl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclyl lower alkyl,substituted or unsubstituted heterocyclyloxy, substituted orunsubstituted phosphoric acid residue, aryl substituted with substitutedor unsubstituted phosphoric acid residue, hydroxy substituted withsubstituted or unsubstituted phosphoric acid residue, amino substitutedwith substituted or unsubstituted phosphoric acid residue, lower alkylsubstituted with substituted or unsubstituted phosphoric acid residue (Aheteroatom group selected from the group consisting of O, S, SO, SO₂,NR⁵ (R⁵ is selected independently from the same substituents group asR⁴), —N═ and ═N— may intervene in the lower alkyl), hydroxy, substitutedor unsubstituted amino, substituted or unsubstituted loweralkylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl,substituted or unsubstituted cycloalkyl lower alkylcarbonyl, substitutedor unsubstituted lower alkoxycarbonyl, substituted or unsubstitutedarylcarbonyl, substituted or unsubstituted aryl lower alkylcarbonyl,substituted or unsubstituted aryloxycarbonyl, substituted orunsubstituted heterocyclylcarbonyl, substituted or unsubstitutedheterocyclyl lower alkylcarbonyl, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstituted aminocarbonyl,substituted or unsubstituted ureido or substituted or unsubstitutedthioureido, preferably, hydrogen, halogen, hydroxy, substituted orunsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, andthe like. A substituent(s) in the “substituted or unsubstituted” onR^(5a), R^(5b), R^(6a), R^(6b), R^(7a), R^(7b), R⁸, R^(9a), R^(9b) andR¹⁰ are halogen, hydroxy, amino, lower alkylamino, cyano, carboxy,formyl, oxo, lower alkyl, lower alkoxy, lower alkylthio, carbamoyl,lower alkylcarbamoyl, aryl, heterocyclyl, lower alkylcarbonyl, loweralkylcarbonyloxy, lower alkoxycarbonyl, halogenated lower alkyl,halogenated lower alkoxy, and the like, more preferably, halogen,hydroxy, amino, lower alkylamino, lower alkyl, lower alkoxy, and thelike.

R^(5a), R^(5b), R^(6a), R^(6b), R^(7a), R^(7b), R⁸, R^(9a), R^(9b) andR¹⁰ are more preferably, each independently, hydrogen, halogen, hydroxy,lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy orsubstituted or unsubstituted amino, further preferably, eachindependently, hydrogen or lower alkyl (e.g., methyl).

R^(5a) and R^(5b), R^(6a) and R^(6b), R^(7a) and R^(7b), and/or R^(9a)and R^(9b) may be taken together to form oxo, thioxo or substituted orunsubstituted spiro ring (example of substituent: halogen, hydroxy,amino, lower alkylamino, cyano, carboxy, formyl, oxo, lower alkyl, loweralkoxy, lower alkylthio, carbamoyl, lower alkylcarbamoyl, aryl,heterocyclyl, lower alkylcarbonyl, lower alkylcarbonyloxy, loweralkoxycarbonyl, halogenated lower alkyl, halogenated lower alkoxy),preferably, oxo or 3- to 5-membered unsubstituted spiro ring.

R^(5b) and R^(6b), R^(6b) and R^(7b) and/or R^(7b) and R^(9b) may betaken together with neighboring atoms to form substituted orunsubstituted carbocycle or substituted or unsubstituted heterocycle,and/or R^(5b) and R^(7b), R^(5b) and R⁸, R^(5b) and R^(9b), R^(6b) andR⁸, R^(6b) and R^(9b) or R^(7b) and R⁸ may be taken together to formsubstituted or unsubstituted (C2-C4) bridge,

R^(5b) and R¹⁰ may be taken together with neighboring atoms to formsubstituted or unsubstituted heterocycle, or R^(6b) and R¹⁰, or R^(7b)and R¹⁰ may be taken together to form substituted or unsubstituted(C2-C4) bridge.

Example of substituent of “substituted or unsubstituted carbocycle”,“substituted or unsubstituted heterocycle” or “substituted orunsubstituted (C2-C4) bridge” is halogen, hydroxy, amino, loweralkylamino, cyano, carboxy, formyl, oxo, lower alkyl, lower alkoxy,lower alkylthio, carbamoyl, lower alkylcarbamoyl, aryl, heterocyclyl,lower alkylcarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyl,halogenated lower alkyl, halogenated lower alkoxy, and the like, morepreferably, halogen, hydroxy, amino, lower alkylamino, lower alkyl,lower alkoxy, and the like.

R^(x) is hydrogen or substituted or unsubstituted lower alkyl,preferably, hydrogen.

The compound of formula (I-1) is, further preferably, the compoundrepresented by any following formula.

When either one of B¹ and B² is CR²⁰R²¹ and the other is NR²²,preferably B¹ is CR²⁰R²¹, B² is NR²².

When B² is NR²², R⁴ and R²² may be taken together with neighboring atomsto form substituted or unsubstituted heterocycle (e.g., F ring).

When B¹ is CR²⁰R²¹ and B² is NR²², or B¹ is NR²² and B² is CR²⁰R²¹, R²⁰and R²² may be taken together with neighboring atoms to form substitutedor unsubstituted heterocycle (e.g., G ring). When B² is CR²⁰R²¹, R⁴ andR²¹ may be taken together with neighboring atom to form substituted orunsubstituted heterocycle.

When either one of B¹ and B² is CR²³ and the other is N, the broken linerepresents the presence of a bond; when B² is CR²³, R⁴ and R²³ may betaken together with neighboring atoms to form substituted orunsubstituted heterocycle.

B¹ and B² are each independently CR²⁰R²¹ or CR²³.

R³ is hydrogen, halogen, hydroxy, substituted or unsubstituted loweralkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy,substituted or unsubstituted lower alkenyloxy, substituted orunsubstituted aryl, substituted or unsubstituted aryloxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted heterocyclyloxyor substituted or unsubstituted amino. Examples of a substituent(s) inthe “substituted or unsubstituted” on R³ include halogen, hydroxy,amino, lower alkylamino, cyano, carboxy, formyl, oxo, lower alkyl, loweralkoxy, lower alkylthio, carbamoyl, lower alkylcarbamoyl, aryl,heterocyclyl, lower alkylcarbonyl, lower alkylcarbonyloxy, loweralkoxycarbonyl, halogenated lower alkyl, halogenated lower alkoxy, andthe like, more preferably, halogen, hydroxy, amino, lower alkylamino,lower alkyl, lower alkoxy, and the like.

R³ is more preferably, hydrogen, halogen, hydroxy, lower alkyl, loweralkenyl, lower alkoxy, lower alkenyloxy or amino, further preferably,hydrogen or lower alkyl (e.g., methyl), particularly preferably,hydrogen.

R⁴ is hydrogen, substituted or unsubstituted lower alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl loweralkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkoxy, substituted or unsubstituted aryl,substituted or unsubstituted aryl lower alkyl, substituted orunsubstituted aryloxy, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclyl lower alkyl, substituted orunsubstituted heterocyclyloxy, hydroxy, substituted or unsubstitutedamino, substituted or unsubstituted phosphoric acid residue, arylsubstituted with substituted or unsubstituted phosphoric acid residue,hydroxy substituted with substituted or unsubstituted phosphoric acidresidue, amino substituted with substituted or unsubstituted phosphoricacid residue or lower alkyl substituted with substituted orunsubstituted phosphoric acid residue (A heteroatom group selected fromthe group consisting of CO, O, S, SO, SO₂, NR^(a) (R^(a) is hydrogen orlower alkyl), —N═ and ═N— may intervene in the lower alkyl), morepreferably, hydrogen, substituted or unsubstituted lower alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkyl lower alkyl, substituted or unsubstituted lower alkenyl,substituted or unsubstituted aryl, substituted or unsubstituted aryllower alkyl, substituted or unsubstituted heterocyclyl or substituted orunsubstituted heterocyclyl lower alkyl.

R⁴ is, preferably, substituted or unsubstituted lower alkyl (e.g.,methyl, ethyl, n-propyl, i-propyl, n-butyl; example of substituent:hydroxy, amino, lower alkylamino, lower alkoxy, aryloxy, oxo, loweralkoxycarbonyl, substituted or unsubstituted heterocyclylcarbonyl(example of substituent: lower alkyl, lower alkoxy)), specifically,lower alkylamino lower alkyl (e.g., 2-dimethylaminoethyl,2-diethylaminoethyl), lower alkoxy lower alkyl (e.g., 1-methoxyethyl,2-methoxypropyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl,2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 2-propoxyethyl,3-propoxypropyl, 4-propoxybutyl) or aryloxy lower alkyl (e.g.,2-phenoxyethyl, 3-phenoxypropyl); substituted or unsubstitutedcycloalkyl (e.g., cyclopropyl); substituted or unsubstituted cycloalkyllower alkyl (e.g., cyclopropylmethyl, 1-adamantylmethyl,2-adamantylmethyl, dodecahedranemethyl, cubanemethyl); substituted orunsubstituted aryl (e.g., phenyl; example of substituent: lower alkyl,halogen, lower alkyloxy, nitro; or a substituent part may be loweralkylene that may be intervened by a heteroatom (e.g., O)); substitutedor unsubstituted aryl lower alkyl (e.g., benzyl; example of substituent:lower alkyl, halogen, lower alkyloxy, nitro; or a substituent part maybe lower alkylene that may be intervened by a heteroatom (e.g., O)); ansubstituted or unsubstituted heterocyclic group (preferably 5- to6-membered ring) (e.g., picolyl, pyridyl; example of substituent: loweralkyl, halogen, lower alkyloxy, nitro); or an substituted orunsubstituted heterocyclic group (preferably 5- to 6-membered ring)lower alkyl (e.g., piperonylmethyl, 2-morpholinoethyl, thiophenemethyl,furanmethyl, tetrahydrofuranmethyl, dioxanemethyl,tetrahydropyranmethyl, thiazolemethyl, oxazolemethyl,1,2,4-oxadiazolemethyl, 1,3,4-oxadiazolemethyl; example of substituent:lower alkyl, halogen, lower alkyloxy, nitro; and the heterocycle may becondensed to a benzene ring).

R²⁰, R²¹, R²² and R²³ are each independently, hydrogen, halogen,substituted or unsubstituted lower alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkyl lower alkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedlower alkoxy, substituted or unsubstituted lower alkenyloxy, substitutedor unsubstituted aryl, substituted or unsubstituted aryl lower alkyl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclyl lower alkyl,substituted or unsubstituted heterocyclyloxy, substituted orunsubstituted phosphoric acid residue, aryl substituted with substitutedor unsubstituted phosphoric acid residue, hydroxy substituted withsubstituted or unsubstituted phosphoric acid residue, amino substitutedwith substituted or unsubstituted phosphoric acid residue, lower alkylsubstituted with substituted or unsubstituted phosphoric acid residue (Aheteroatom group selected from the group consisting of O, S, SO, SO₂,NR⁵ (R⁵ is selected independently from the same substituents group asR⁴), —N═ and ═N— may intervene in the lower alkyl), hydroxy, substitutedor unsubstituted amino, substituted or unsubstituted loweralkylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl,substituted or unsubstituted cycloalkyl lower alkylcarbonyl, substitutedor unsubstituted lower alkoxycarbonyl, substituted or unsubstitutedarylcarbonyl, substituted or unsubstituted aryl lower alkylcarbonyl,substituted or unsubstituted aryloxycarbonyl, substituted orunsubstituted heterocyclylcarbonyl, substituted or unsubstitutedheterocyclyl lower alkylcarbonyl, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstituted aminocarbonyl,substituted or unsubstituted ureido or substituted or unsubstitutedthioureido.

R²⁰, R²¹, R²² and R²³ are preferably, each independently, hydrogen,substituted or unsubstituted lower alkyl (example of substituent: amino,lower alkylamino, lower carbonylamino, lower alkoxy, aryloxy, cyano,halogen, acylamino (e.g., lower carbonylamino), lower alkynyl, hydroxy,lower alkoxycarbonyl, substituted or unsubstituted heterocyclylcarbonyl(example of substituent: lower alkyl, lower alkoxy), lower alkenyl,substituted or unsubstituted carbamoyl (example of substituent: loweralkyl), lower alkylcarbonyloxy, lower alkyloxycarbonyl, loweralkylcarbonylamino, oxo, lower alkynyl), cycloalkyl, cycloalkyl loweralkyl, substituted or unsubstituted aryl (example of substituent: loweralkyl, halo gen, lower alkyloxy, nitro), substituted or unsubstitutedaryl lower alkyl (example of substituent: lower alkyl, halogen, loweralkyloxy, nitro, oxo), substituted or unsubstituted heterocyclyl(example of substituent: lower alkyl, halogen, lower alkyloxy, nitro),substituted or unsubstituted heterocyclyl lower alkyl (example ofsubstituent: lower alkyl, halogen, lower alkyloxy, nitro, oxo),substituted or unsubstituted lower alkylcarbonyl (substituent: loweralkoxy, halogen), cycloalkylcarbonyl, substituted or unsubstitutedbenzoyl (substituent: lower alkoxy, halogen), substituted sulfonyl(substituent: lower alkyl, aryl, heterocyclyl (preferably 5- to6-membered aromatic heterocyclyl)).

R²⁰ and R²¹ are more preferably, hydrogen.

The broken line represents the presence or absence of a bond, morepreferably, represents the absence of a bond.

When B¹ is NR²², the broken line represents the absence of a bond, thecompound whose R⁴ is unsubstituted ethyl or unsubstituted isopropyl areexcluded from the present compound.

B¹ and B² are defined at the same as formula (I-3).

F ring is substituted or unsubstituted heterocycle, preferably, thefollowing 5- to 7-membered substituted or unsubstituted heterocycle.

Z¹, Z², Z³, Z⁴ and Z⁵ are each independently, CR¹R², CR¹, O, S, SO, SO₂,N or NR¹⁹.

Z¹ is preferably, CR¹R², O, S or NR¹⁹, and more preferably is CR¹R².

Z² is preferably, CR¹R², O, S or NR¹⁹, and more preferably is CR¹R².

Z³ is preferably, CR¹R², O, S or NR¹⁹, and more preferably is CR¹R² orO.

Z⁴ is preferably, CR¹R², O, S or NR¹⁹, and more preferably is CR¹R², Oor NR¹⁹, and particularly preferably is CR¹R² or O.

Z⁵ is preferably, CR¹R², O, S or NR¹⁹, and more preferably is CR¹R² orO.

Z¹ and Z³, Z¹ and Z⁴, Z¹ and Z⁵, Z² and Z⁴, Z² and Z⁵, or Z³ and Z⁵ maybe taken together to form substituted or unsubstituted (C2-C4) bridge(example of substituent: lower alkyl, hydroxy, halogen).

R¹ and R² may be a variety of substituents as far as they do notadversely affect on the pharmacological activity of the presentcompound. Examples thereof include, for example, each independently,hydrogen, halogen, substituted or unsubstituted lower alkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyllower alkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkoxy, substituted or unsubstituted loweralkenyloxy, substituted or unsubstituted aryl, substituted orunsubstituted aryl lower alkyl, substituted or unsubstituted aryloxy,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclyl lower alkyl, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted phosphoric acid residue, aryl substitutedwith substituted or unsubstituted phosphoric acid residue, hydroxysubstituted with substituted or unsubstituted phosphoric acid residue,amino substituted with substituted or unsubstituted phosphoric acidresidue, lower alkyl substituted with substituted or unsubstitutedphosphoric acid residue (A heteroatom group selected from the groupconsisting of O, S, SO, SO₂, NR⁵ (R⁵ is selected independently from thesame substituents group as R⁴), —N═ and ═N— may intervene in the loweralkyl), hydroxy, substituted or unsubstituted amino, substituted orunsubstituted lower alkylcarbonyl, substituted or unsubstitutedcycloalkylcarbonyl, substituted or unsubstituted cycloalkyl loweralkylcarbonyl, substituted or unsubstituted lower alkoxycarbonyl,substituted or unsubstituted arylcarbonyl, substituted or unsubstitutedaryl lower alkylcarbonyl, substituted or unsubstituted aryloxycarbonyl,substituted or unsubstituted heterocyclylcarbonyl, substituted orunsubstituted heterocyclyl lower alkylcarbonyl, substituted orunsubstituted heterocyclyloxycarbonyl, substituted or unsubstitutedaminocarbonyl, substituted or unsubstituted ureido or substituted orunsubstituted thioureido, preferably, hydrogen, halogen, hydroxy,substituted or unsubstituted lower alkyl, substituted or unsubstitutedcycloalkyl, and the like.

Examples of a substituent(s) in the “substituted or unsubstituted” on R¹and R² include halogen, hydroxy, amino, lower alkylamino, cyano,carboxy, formyl, oxo, lower alkyl, lower alkoxy, lower alkylthio,carbamoyl, lower alkylcarbamoyl, aryl, heterocyclyl, loweralkylcarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyl, halogenatedlower alkyl, halogenated lower alkoxy, and the like, more preferably,halogen, hydroxy, amino, lower alkylamino, lower alkyl, lower alkoxy,and the like.

R¹ and R² are more preferably, each independently, hydrogen, halogen,hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy orsubstitute d or unsubstituted amino, further preferably, eachindependently, hydrogen or lower alkyl (e.g., methyl), particularlypreferably, hydrogen.

R¹ and R² may be taken together to form oxo, thioxo or substituted orunsubstituted spiro ring (example of substituent: lower alkyl, halogen,halogenated lower alkyl, hydroxy, amino), preferably, oxo orunsubstituted spiro ring.

R¹⁹ is preferably, 1) hydrogen, 2) substituted or unsubstituted loweralkyl (example of substituent: amino substituted or unsubstituted withmono- or di-lower alkyl, cycloalkyl, hydroxy, an substituted orunsubstituted heterocyclic group (wherein the heterocycle is preferablya 5- to 7-membered ring; example: furyl, thienyl, thiazolyl, pyridyl,morpholino, imidazole; example of substituent: lower alkyl, halogen),substituted or unsubstituted heterocyclylcarbonyl (wherein theheterocycle is preferably a 5- to 7-membered ring; example:morpholinocarbonyl), substituted or unsubstituted phenyl (substituent:lower alkyl, amino, lower alkylamino, hydroxy, halogen, halogenatedlower alkyl, lower alkoxy, halogenated lower alkoxy, lower alkylthio,lower alkylsulfonyl), acetylamino, carbamoyl, mono- or di-loweralkyl-substituted carbamoyl, lower alkylsulfonylamino, lower alkoxy,carbonyl, halogen, thiol, lower alkylthio), 3) lower alkenyl, 4) acyl(e.g., lower alkylcarbonyl), or 5) lower alkylsulfonyl. R¹⁹ may beselected from the Substituent group S2 described below.

The broken line represents the presence or absence of a bond, preferablyrepresents the absence of a bond.

Further, F ring may have H ring as the following. In this case, Z¹, Z²,Z³, Z⁴ and Z⁵ constituting H ring are each independently, CR¹, C or N.

H ring is each independently, substituted or unsubstituted carbocycle orsubstituted or unsubstituted heterocycle, preferably, substituted orunsubstituted 4- to 7-membered carbocycle (example of substituent: loweralkyl, halogen, hydroxy, halogenated lower alkyl) or substituted orunsubstituted 4- to 7-membered heterocycle (example of substituent:lower alkyl, halogen, hydroxy, halogenated lower alkyl), morepreferably, 5- to 6-membered unsubstituted carbocycle or 5- to6-membered unsubstituted heterocycle, particularly preferably,5-membered unsubstituted carbocycle or 5-membered unsubstitutedheterocycle.

G ring is substituted or unsubstituted carbocycle or substituted orunsubstituted heterocycle. B¹ is CR²¹ or N. When B¹ is CR²¹, B² is N.When B¹ is N, B² is CR²¹. The same heterocycle of F ring is exemplifiedfor G ring. The substituent on G ring is the same or different, one tofour, further preferably one or two, substituent(s) selected fromSubstituent group S2. The part of substituent on G ring may be takentogether with neighboring atoms to form, further condensed ring or spiroring, preferably substituted or unsubstituted carbocycle (preferably 5-to 6-membered ring) or substituted or unsubstituted heterocycle(preferably 5- to 6-membered ring).

When G ring is carbocycle, B¹ and B² are each independently C or CH. 5-to 7-membered ring as carbocycle are exampled.

G ring including the following rings.

Preferable substituent on G ring is lower alkyl (e.g., methyl,isopropyl), lower alkoxylower alkyl (e.g., 2-methoxyethyl), substitutedor unsubstituted amino (example of substituent: lower alkyl (e.g.,methyl), lower alkylcarbonyl (e.g., acetyl)).

R³ is preferably, hydrogen or substituted or unsubstituted lower alkyl,more preferably hydrogen.

R⁴ is, preferably, substituted or unsubstituted lower alkyl (e.g.,methyl, ethyl, n-propyl, i-propyl, n-butyl; example of substituent:hydroxy, amino, lower alkylamino, lower alkoxy, aryloxy, oxo, loweralkoxycarbonyl, substituted or unsubstituted heterocyclylcarbonyl(example of substituent: lower alkyl, lower alkoxy)), specifically,lower alkylamino lower alkyl (e.g., 2-dimethylaminoethyl,2-diethylaminoethyl), lower alkoxy lower alkyl (e.g., 1-methoxyethyl,2-methoxypropyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl,2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 2-propoxyethyl,3-propoxypropyl, 4-propoxybutyl) or aryloxy lower alkyl (e.g.,2-phenoxyethyl, 3-phenoxypropyl); substituted or unsubstitutedcycloalkyl (e.g., cyclopropyl); substituted or unsubstituted cycloalkyllower alkyl (e.g., cyclopropylmethyl, 1-adamantylmethyl,2-adamantylmethyl, dodecahedranemethyl, cubanemethyl); substituted orunsubstituted aryl (e.g., phenyl; example of substituent: lower alkyl,halogen, lower alkyloxy, nitro; or a substituent part may be loweralkylene that may be intervened by a heteroatom (e.g., O)); substitutedor unsubstituted aryl lower alkyl (e.g., benzyl; example of substituent:lower alkyl, halogen, lower alkyloxy, nitro; or a substituent part maybe lower alkylene that may be intervened by a heteroatom (e.g., O)); ansubstituted or unsubstituted heterocyclic group (preferably 5- to6-membered ring) (e.g., picolyl, pyridyl; example of substituent: loweralkyl, halogen, lower alkyloxy, nitro); or an substituted orunsubstituted heterocyclic group (preferably 5- to 6-membered ring)lower alkyl (e.g., piperonylmethyl, 2-morpholinoethyl, thiophenemethyl,furanmethyl, tetrahydrofuranmethyl, dioxanemethyl,tetrahydropyranmethyl, thiazolemethyl, oxazolemethyl,1,2,4-oxadiazolemethyl, 1,3,4-oxadiazolemethyl; example of substituent:lower alkyl, halogen, lower alkyloxy, nitro; and the heterocycle may becondensed to a benzene ring).

R¹¹, R^(12a), R^(12b) and R¹³ are each independently, hydrogen, halogen,substituted or unsubstituted lower alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkyl lower alkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedlower alkoxy, substituted or unsubstituted lower alkenyloxy, substitutedor unsubstituted aryl, substituted or unsubstituted aryl lower alkyl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclyl lower alkyl,substituted or unsubstituted heterocyclyloxy, substituted orunsubstituted phosphoric acid residue, aryl substituted with substitutedor unsubstituted phosphoric acid residue, hydroxy substituted withsubstituted or unsubstituted phosphoric acid residue, amino substitutedwith substituted or unsubstituted phosphoric acid residue, lower alkylsubstituted with substituted or unsubstituted phosphoric acid residue (Aheteroatom group selected from the group consisting of O, S, SO, SO₂,NR⁵ (R⁵ is selected independently from the same substituents group asR⁴), —N═ and ═N— may intervene in the lower alkyl), hydroxy, substitutedor unsubstituted amino, substituted or unsubstituted loweralkylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl,substituted or unsubstituted cycloalkyl lower alkylcarbonyl, substitutedor unsubstituted lower alkoxycarbonyl, substituted or unsubstitutedarylcarbonyl, substituted or unsubstituted aryl lower alkylcarbonyl,substituted or unsubstituted aryloxycarbonyl, substituted orunsubstituted heterocyclylcarbonyl, substituted or unsubstitutedheterocyclyl lower alkylcarbonyl, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstituted aminocarbonyl,substituted or unsubstituted ureido or substituted or unsubstitutedthioureido.

R¹¹ is preferably, substituted or unsubstituted lower alkyl (e.g.,methyl, n-propyl, n-buthyl (proviso ethyl and isopropyl are excluded);example of substituent:hydroxy, amino, lower alkylamino, lower alkoxy,aryloxy, oxo, lower alkoxycarbonyl, substituted or unsubstitutedheterocyclylcarbonyl (example of substituent: lower alkyl, loweralkoxy), specifically, lower alkylaminolower alkyl (e.g.,2-dimethylaminoethyl, 2-diethylaminoethyl), lower alkoxylower alkyl(e.g., 1-methoxyethyl, 2-methoxypropyl, 2-methoxyethyl, 3-methoxypropyl,4-methoxybuthyl, 2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybuthyl,2-propoxyethyl, 3-propoxypropyl, 4-propoxybutyl) or aryloxylower alkyl(e.g., 2-phenoxyethyl, 3-phenoxypropyl); substituted or unsubstitutedcycloalkyl (e.g., cyclopropyl); substituted or unsubstituted cycloalkyllower alkyl (e.g., cyclopropylmethyl, 1-adamantylmethyl,2-adamantylmethyl, dodecahedranemethyl, cubanemethyl); substituted orunsubstituted aryl (e.g., phenyl; example of substituent: lower alkyl,halogen, lower alkyloxy, nitro; or a substituent part may be loweralkylene that may be intervened by a heteroatom (e.g., O)); substitutedor unsubstituted aryl lower alkyl (e.g., benzyl; example of substituent:lower alkyl, halogen, lower alkyloxy, nitro; or a substituent part maybe lower alkylene that may be intervened by a heteroatom (e.g., O));substituted or unsubstituted heterocyclyl (preferably 5- to 6-memberedring) (e.g., picolyl, pyridyl; example of substituent: lower alkyl,halogen, lower alkyloxy, nitro); or an substituted or unsubstitutedheterocyclic group (preferably 5- to 6-membered ring) lower alkyl (e.g.,piperonylmethyl, 2-morpholinoethyl, thiophenemethyl, furanmethyl,tetrahydrofuranmethyl, dioxanemethyl, tetrahydropyranmethyl,thiazolemethyl, oxazolemethyl, 1,2,4-oxadiazolemethyl,1,3,4-oxadiazolemethyl; example of substituent: lower alkyl, halogen,lower alkyloxy, nitro; and the heterocycle may be condensed to a benzenering).

R^(12a) and R^(12b) are preferably, each independently, hydrogen,substituted or unsubstituted lower alkyl (example of substituent: amino,lower alkylamino, lower carbonylamino, lower alkoxy, aryloxy, cyano,halogen, acylamino (e.g., lower carbonylamino), lower alkynyl, hydroxy,lower alkoxycarbonyl, substituted or unsubstituted heterocyclylcarbonyl(example of substituent: lower alkyl, lower alkoxy), lower alkenyl,substituted or unsubstituted carbamoyl (example of substituent: loweralkyl), lower alkylcarbonyloxy, lower alkyloxycarbonyl, loweralkylcarbonylamino, oxo, lower alkynyl), cycloalkyl, cycloalkyl loweralkyl, substituted or unsubstituted aryl (example of substituent: loweralkyl, halogen, lower alkyloxy, nitro), substituted or unsubstitutedaryl lower alkyl (example of substituent: lower alkyl, halogen, loweralkyloxy, nitro, oxo), substituted or unsubstituted heterocyclyl(example of substituent: lower alkyl, halogen, lower alkyloxy, nitro),substituted or unsubstituted heterocyclyl lower alkyl (example ofsubstituent: lower alkyl, halogen, lower alkyloxy, nitro, oxo),substituted or unsubstituted lower alkylcarbonyl (substituent: loweralkoxy, halogen), cycloalkylcarbonyl, substituted or unsubstitutedbenzoyl (substituent: lower alkoxy, halogen), substituted sulfonyl(substituent: lower alkyl, aryl, heterocyclyl (preferably 5- to6-membered aromatic heterocyclyl)).

More preferably, R^(12a) and R^(12b) are hydrogen.

R^(12a) and R^(12b) may be taken together to form oxo or thioxo.

R¹¹, R^(12a), R^(12b) and R¹³ are each independently, hydrogen, halogen,substituted or unsubstituted lower alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkyl lower alkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedlower alkoxy, substituted or unsubstituted lower alkenyloxy, substitutedor unsubstituted aryl, substituted or unsubstituted aryl lower alkyl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclyl lower alkyl,substituted or unsubstituted heterocyclyloxy, substituted orunsubstituted phosphoric acid residue, aryl substituted with substitutedor unsubstituted phosphoric acid residue, hydroxy substituted withsubstituted or unsubstituted phosphoric acid residue, amino substitutedwith substituted or unsubstituted phosphoric acid residue, lower alkylsubstituted with substituted or unsubstituted phosphoric acid residue (Aheteroatom group selected from the group consisting of O, S, SO, SO₂,NR⁵ (R⁵ is selected independently from the same substituents group asR⁴), —N═ and ═N— may intervene in the lower alkyl), hydroxy, substitutedor unsubstituted amino, substituted or unsubstituted loweralkylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl,substituted or unsubstituted cycloalkyl lower alkylcarbonyl, substitutedor unsubstituted lower alkoxycarbonyl, substituted or unsubstitutedarylcarbonyl, substituted or unsubstituted aryl lower alkylcarbonyl,substituted or unsubstituted aryloxycarbonyl, substituted orunsubstituted heterocyclylcarbonyl, substituted or unsubstitutedheterocyclyl lower alkylcarbonyl, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstituted aminocarbonyl,substituted or unsubstituted ureido or substituted or unsubstitutedthioureido.

R¹¹ is preferably, substituted or unsubstituted lower alkyl (e.g.,methyl, n-propyl, n-buthyl (proviso ethyl and isopropyl are excluded);example of substituent: hydroxy, amino, lower alkylamino, lower alkoxy,aryloxy, oxo, lower alkoxycarbonyl, substituted or unsubstitutedheterocyclylcarbonyl (example of substituent: lower alkyl, loweralkoxy), specifically, lower alkylaminolower alkyl (e.g.,2-dimethylaminoethyl, 2-diethylaminoethyl), lower alkoxylower alkyl(e.g., 1-methoxyethyl, 2-methoxypropyl, 2-methoxyethyl, 3-methoxypropyl,4-methoxybuthyl, 2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybuthyl,2-propoxyethyl, 3-propoxypropyl, 4-propoxybutyl) or aryloxylower alkyl(e.g., 2-phenoxyethyl, 3-phenoxypropyl); substituted or unsubstitutedcycloalkyl (e.g., cyclopropyl); substituted or unsubstituted cycloalkyllower alkyl (e.g., cyclopropylmethyl, 1-adamantylmethyl,2-adamantylmethyl, dodecahedranemethyl, cubanemethyl); substituted orunsubstituted aryl (e.g., phenyl; example of substituent: lower alkyl,halogen, lower alkyloxy, nitro; or a substituent part may be loweralkylene that may be intervened by a heteroatom (e.g., O)); substitutedor unsubstituted aryl lower alkyl (e.g., benzyl; example of substituent:lower alkyl, halogen, lower alkyloxy, nitro; or a substituent part maybe lower alkylene that may be intervened by a heteroatom (e.g., O));substituted or unsubstituted heterocyclyl (preferably 5- to 6-memberedring) (e.g., picolyl, pyridyl; example of substituent: lower alkyl,halogen, lower alkyloxy, nitro); or an substituted or unsubstitutedheterocyclic group (preferably 5- to 6-membered ring) lower alkyl (e.g.,piperonylmethyl, 2-morpholinoethyl, thiophenemethyl, furanmethyl,tetrahydrofuranmethyl, dioxanemethyl, tetrahydropyranmethyl,thiazolemethyl, oxazolemethyl, 1,2,4-oxadiazolemethyl,1,3,4-oxadiazolemethyl; example of substituent: lower alkyl, halogen,lower alkyloxy, nitro; and the heterocycle may be condensed to a benzenering).

R^(12a) and R^(12b) are preferably, each independently, hydrogen,substituted or unsubstituted lower alkyl (example of substituent: amino,lower alkylamino, lower carbonylamino, lower alkoxy, aryloxy, cyano,halogen, acylamino (e.g., lower carbonylamino), lower alkynyl, hydroxy,lower alkoxycarbonyl, substituted or unsubstituted heterocyclylcarbonyl(example of substituent: lower alkyl, lower alkoxy), lower alkenyl,substituted or unsubstituted carbamoyl (example of substituent: loweralkyl), lower alkylcarbonyloxy, lower alkyloxycarbonyl, loweralkylcarbonylamino, oxo, lower alkynyl), cycloalkyl, cycloalkyl loweralkyl, substituted or unsubstituted aryl (example of substituent: loweralkyl, halogen, lower alkyloxy, nitro), substituted or unsubstitutedaryl lower alkyl (example of substituent: lower alkyl, halogen, loweralkyloxy, nitro, oxo), substituted or unsubstituted heterocyclyl(example of substituent: lower alkyl, halogen, lower alkyloxy, nitro),substituted or unsubstituted heterocyclyl lower alkyl (example ofsubstituent: lower alkyl, halogen, lower alkyloxy, nitro, oxo),substituted or unsubstituted lower alkylcarbonyl (substituent: loweralkoxy, halogen), cycloalkylcarbonyl, substituted or unsubstitutedbenzoyl (substituent: lower alkoxy, halogen), substituted sulfonyl(substituent: lower alkyl, aryl, heterocyclyl (preferably 5- to6-membered aromatic heterocyclyl)).

More preferably, R^(12a) and R^(12b) are hydrogen.

R^(12a) and R^(12b) may be taken together to form oxo, thioxo orsubstituted or unsubstituted spiro ring (example of substituent:halogen, hydroxy, amino, lower alkylamino, cyano, carboxy, formyl, oxo,lower alkyl, lower alkoxy, lower alkylthio, carbamoyl, loweralkylcarbamoyl, aryl, heterocyclyl, lower alkylcarbonyl, loweralkylcarbonyloxy, lower alkoxycarbonyl, halogenated lower alkyl,halogenated lower alkoxy, and the like, more preferably, halogen,hydroxy, amino, lower alkylamino, lower alkyl, lower alkoxy, and thelike).

X is CR^(18a)R^(18b), NR²⁴, O or S, preferably, is CR^(18a)R^(18b) or O.

R^(15a), R^(15b), R^(16a), R^(16b), R^(17a), R^(17b), R^(18a), R^(18b)and R²⁴ may be a variety of substituents as far as they do not adverselyaffect on the pharmacological activity of the present compound. Examplesthereof include, for example, each independently, hydrogen, halogen,substituted or unsubstituted lower alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkyl lower alkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedlower alkoxy, substituted or unsubstituted lower alkenyloxy, substitutedor unsubstituted aryl, substituted or unsubstituted aryl lower alkyl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclyl lower alkyl,substituted or unsubstituted heterocyclyloxy, substituted orunsubstituted phosphoric acid residue, aryl substituted with substitutedor unsubstituted phosphoric acid residue, hydroxy substituted withsubstituted or unsubstituted phosphoric acid residue, amino substitutedwith substituted or unsubstituted phosphoric acid residue, lower alkylsubstituted with substituted or unsubstituted phosphoric acid residue (Aheteroatom group selected from the group consisting of O, S, SO, SO₂,NR⁵ (R⁵ is selected independently from the same substituents group asR⁴), —N═ and ═N— may intervene in the lower alkyl), hydroxy, substitutedor unsubstituted amino, substituted or unsubstituted loweralkylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl,substituted or unsubstituted cycloalkyl lower alkylcarbonyl, substitutedor unsubstituted lower alkoxycarbonyl, substituted or unsubstitutedarylcarbonyl, substituted or unsubstituted aryl lower alkylcarbonyl,substituted or unsubstituted aryloxycarbonyl, substituted orunsubstituted heterocyclylcarbonyl, substituted or unsubstitutedheterocyclyl lower alkylcarbonyl, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstituted aminocarbonyl,substituted or unsubstituted ureido or substituted or unsubstitutedthioureido.

R^(15a), R^(15b), R^(16a), R^(16b), R^(17a), R^(17b), R^(18a), R^(18b)and R²⁴ are preferably, each independently, hydrogen, halogen, hydroxy,substituted or unsubstituted lower alkyl, substituted or unsubstitutedcycloalkyl, and the like. Examples of a substituent(s) in the“substituted or unsubstituted” on R^(15a), R^(15b), R^(16a), R^(16b),R^(17a), R^(17b), R^(18a), R^(18b) or R²⁴ include halogen, hydroxy,amino, lower alkylamino, cyano, carboxy, formyl, oxo, lower alkyl, loweralkoxy, lower alkylthio, carbamoyl, lower alkylcarbamoyl, aryl,heterocyclyl, lower alkylcarbonyl, lower alkylcarbonyloxy, loweralkoxycarbonyl, halogenated lower alkyl, halogenated lower alkoxy, andthe like, more preferably, halogen, hydroxy, amino, lower alkylamino,lower alkyl, lower alkoxy, and the like.

R^(15a), R^(15b), R^(16a), R^(16b), R^(17a), R^(17b), R^(18a), R^(18b)and R²⁴ are more preferably, each independently, hydrogen, halogen,hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy orsubstituted or unsubstituted amino, further preferably, eachindependently, hydrogen or lower alkyl (e.g., methyl).

R^(15a) and R^(15b), R^(16a) and R^(16b), R^(17a) and R^(17b), orR^(18a) and R^(18b) may be taken together to form oxo, thioxo orsubstituted or unsubstituted spiro ring.

R^(15b) and R^(16b), R^(16b) and R^(18b), and/or R^(17b) and R^(18b) maybe taken together to form substituted or unsubstituted carbocycle orsubstituted or unsubstituted heterocycle, or R^(15b) and R^(17b),R^(15b) and R^(18b), or R^(16b) and R^(17b) may be taken together toform substituted or unsubstituted (C2-C4) bridge.

R^(16b) and R²⁴, or R^(17b) and R²⁴ may be taken together to formsubstituted or unsubstituted heterocycle, or R^(15b) and R²⁴ may betaken together to form substituted or unsubstituted (C2-C4) bridge.

In this case, example of substituent of “substituted or unsubstitutedcarbocycle”, “substituted or unsubstituted heterocycle”, “substituted orunsubstituted (C2-C4) bridge” or “substituted or unsubstituted spiroring” is halogen, hydroxy, amino, lower alkylamino, cyano, carboxy,formyl, oxo, lower alkyl, lower alkoxy, lower alkylthio, carbamoyl,lower alkylcarbamoyl, aryl, heterocyclyl, lower alkylcarbonyl, loweralkylcarbonyloxy, lower alkoxycarbonyl, halogenated lower alkyl,halogenated lower alkoxy, and the like, more preferably, halogen,hydroxy, amino, lower alkylamino, lower alkyl, lower alkoxy, and thelike.

Example of formula (I-3), (I-3-1), (I-3-2), (I-3-3), (I-3-4), (I-3-5)and (I-3-6) are specifically exemplified as following formula.

(Embodiment of the Combination Core Structure and Side Chain)

The present compound is including the compound combined any one of theabove core structures formula (I-1-2) to (I-1-8), (I-2-2) to (I-2-14),(I-3-7) to (I-3-15) and (I-4-1) to (I-4-4) with any one of the sidechains formula (Q1) to (Q30).

(Prodrug)

The present compound includes prodrug. Specifically, the compound or itspharmaceutically acceptable salt represented by any one of the followingformula (I 1′), (I-2′) or (I-3′):

wherein Y is any groups of the following:

wherein R^(Y) is substituted or unsubstituted alkyl (example ofsubstituent: halogen, hydroxy, carboxy, cyano, amino, alkyloxy, aromaticcarbocyclyl, unsubstituted aromatic carbocyclyl, aromatic heterocyclyl,unsubstituted aromatic heterocyclyl).

The other symbols are defined the same as the above item [1].

R^(Y) is preferably, methyl, ethyl, n-propyl, isopropyl, n-buthyl,isobuthyl, sec-buthyl, tert-buthyl, or methoxyethyl.

R^(Y) is further preferably, methyl, tert-buthyl, or methoxyethyl.

The present compound has at least the following characteristics as itschemical structure:

(1) the condensed heterocycle, which is the main backbone, issubstituted with oxo (═O), hydroxy (OH), and oxo (═O); and(2) an adjacent position to oxo on the condensed heterocycle has acyclic group represented by -Q. Q is preferably an substituted orunsubstituted heterocyclic group.By possession of such a structure, the present compound exhibitsremarkably potent integrase inhibitory activity and/or cellproliferation inhibitory activity against viruses including HIV(preferably HIV-1). Preferably, it is also effective against resistantbacteria. Meanwhile, the structures of other parts (R³, R¹⁴, R^(X), Aring, D ring, E ring, F ring, G ring, H ring, B¹, B², etc.) can berelatively freely selected from various structures, may have any kind ofsubstituent, may form a condensed ring, and the condensed ring may befurther substituted.

The present compound or its pharmaceutically acceptable salts may formsolvates (e.g., hydrates or the like), cocrystal and/or crystalpolymorphs. The present invention encompasses those various solvates,cocrystal and crystal polymorphs. “Solvates” may be those wherein anynumbers of solvent molecules (e.g., water molecules or the like) arecoordinated with the present compound or its pharmaceutically acceptablesalts. When the present compound or its pharmaceutically acceptablesalts are allowed to stand in the atmosphere, the compounds may absorbwater, resulting in attachment of adsorbed water or formation ofhydrates. Recrystallization of the present compound or itspharmaceutically acceptable salts may produce crystal polymorphs. Theterm “cocrystal” means that a present compound or salts and acounter-molecule exsist in the same crystal lattice, and it can beformed with any number of counter-molecules. All theoretically possibletautomers, geometrical isomers, stereoisomers, optical isomers,racemates, and the like of the present compound are also within thescope of the invention.

Pharmaceutically acceptable salts of a compound of the present inventioninclude, as basic salts, for example, alkali metal salts such as sodiumsalts, potassium salts, and the like; alkaline-earth metal salts such ascalcium salts, magnesium salts, and the like; ammonium salts; aliphaticamine salts such as trimethylamine salts, triethylamine salts,dicyclohexylamine salts, ethanolamine salts, diethanolamine salts,triethanolamine salts, procaine salts, meglumine salts, diethanolaminesalts, ethylenediamine salts, and the like; aralkylamine salts such asN,N-dibenzylethylenediamine salts, benethamine salts, and the like;heterocyclic aromatic amine salts such as pyridine salts, picolinesalts, quinoline salts, isoquinoline salts, and the like; quaternaryammonium salts such as tetramethylammonium salts, tetraethylammoniumsalts, benzyltrimethylammonium salts, benzyltriethylammonium salts,benzyltributylammonium salts, methyltrioctylammonium salts,tetrabutylammonium salts, and the like; basic amino acid salts such asarginine salts, lysine salts, and the like; and the like. Acid saltsthereof include, for example, inorganic acid salts such ashydrochlorides, sulfates, nitrates, phosphates, carbonates, hydrogencarbonates, and perchlorates, and the like; organic acid salts such asacetates, propionates, lactates, maleates, fumarates, tartrates,malates, citrates, ascorbates, and the like; sulfonates such asmethanesulfonates, isethionates, benzenesulfonates, p-toluenesulfonates,and the like; acidic amino acid salts such as aspartates, glutamates,and the like; and the like.

Solvates of a compound of the present invention include solvates withalcohol, hydrates, and the like.

The compounds of the present invention can be synthesized usingcommercially available reagents and known compounds as raw materials,preferably by the method described in Patent Document 15 or inaccordance with the following method.

(Production Method 1)

Wherein P₁ and P₂ are a hydroxy-protecting group; R and R′ are acarboxy-protecting group; B is R^(5a), R^(5b), R^(6a), R^(6b), R^(7a)and R^(7b); the other symbols are defined the same as above; P₁ and P₂are a group which can be protected and/or deprotected described inProtective Groups in Organic Synthesis, Theodora W Green (John Wiley &Sons) etc., for example, P₁ is arylalkyl, and the like; R, R′ and P₂ arelower alkyl, and the like.

Step 1

Compound ec commercially available or prepared by a known method andacetic acid are added to Compound ea or Compound eb prepared by a knownmethod in the solvent such as chloroform, dichloromethane, THF, and thelike. Compound ed can be obtained by reacting at 0° C. to 40° C.,preferably 10° C. to 30° C. for 0.5 hours to 24 hours, preferably anhour to 12 hours.

Step 2

Compound ee can be obtained from Compound ed by a known deprotectivereaction of a hydroxy-protecting group.

Step 3

Compound of and acetic acid are added to Compound ea or Compound eb inthe solvent such as chloroform, dichloromethane, THF, and the like.Compound eg can be obtained by reacting at 0° C. to 40° C., preferably10° C. to 30° C. for 0.5 hours to 24 hours, preferably an hour to 12hours.

Step 4

Compound eh can be obtained from Compound eg by a known deprotectivereaction of a hydroxy-protecting group.

Wherein P₁ is a hydroxy-protecting group; Hal is halogen; other symbolsare defined the same as above; P₁ is a group which can be protectedand/or deprotected described in Protective Groups in Organic Synthesis,Theodora W Green (John Wiley & Sons) etc., for example, P₁ is arylalkyl,and the like.

Step 1

A palladium catalyst such as Pd(PPh₃)₄, Pd(OAc)₂, Pd(PPh₃)₂Cl₂,Pd(dppf)₂Cl₂, Pd(dtbpf), and the like and base such as potassium aceticacid, sodium acetic acid, potassium carbonate, potassium phosphate, andthe like and bis(pinacolato)diboron were added to Compound ca preparedby a known method in solvent such as dioxane, DMF, DME, tetrahydrofuran,DMSO, and the like or its solvent mixture. Compound cb can be obtainedby reacting at 0° C. to 150° C., preferably 60° C. to 120° C. for 0.5hours to 24 hours, preferably an hour to 12 hours under the nitrogenatmosphere.

Step 2

A palladium catalyst such as Pd(PPh₃)₄, Pd(OAc)₂, Pd(PPh₃)₂Cl₂,Pd(dppf)₂Cl₂, Pd(dtbpf), and the like and base such as potassiumcarbonate, sodium carbonate, cesium carbonate, potassium phosphate, andthe like Compound cc commercially available or prepared by a knownmethod are added to Compound cb in solvent such as dioxane, DMF, DME,tetrahydrofuran, water, and the like or its solvent mixture. Compound cdcan be obtained by reacting at 0° C. to 150° C., preferably 60° C. to120° C. for 0.5 hours to 24 hours, preferably an hour to 12 hours underthe nitrogen atmosphere.

Step 3

Compound ce can be obtained from Compound cd by a known deprotectivereaction of a hydroxy-protecting group.

(Production Method 2)

Wherein R and R′ are a carboxy-protecting group; P₁ is ahydroxy-protecting group; P₂ is an amino-protecting group; other symbolsare defined the same as above; R, R′, P₁ and P₂ are a group which can beprotected and/or deprotected described in Protective Groups in OrganicSynthesis, Theodora W Green (John Wiley & Sons) etc., for example, P₁ isarylalkyl, and the like; P₂ is lower alkyloxycarbonyl, and the like.

Step 1

Compound ab commercially available or prepared by a known method isadded to Compound aa commercially available or prepared by a knownmethod in solvent such as toluene, THF, dioxane, acetonitrile, and thelike or its solvent mixture. Compound ac can be obtained by reacting at20° C. to 110° C., preferably 40° C. to under heat reflux for 0.5 hoursto 24 hours, preferably an hour to 12 hours.

Step 2

After a known general deprotective reaction of an amino-protecting groupto Compound ac, Compound ad can be obtained by reacting at 20° C. to110° C., preferably 80° C. to 110° C. for 0.1 hours to 10 hours,preferably 0.5 hours to 3 hours with tertiary amine such astriethylamine, diisopropylethylamine, N-methylmorpholine, and the likein solvent such as toluene, THF, dioxane, acetonitrile, and the like.

Step 3

Compound ae can be obtained from Compound ad by a known deprotectivereaction of a carboxy-protecting group.

Wherein R is a carboxy-protecting group; P₁ is a hydroxy-protectinggroup; P₂ is an amino-protecting group; Hal is halogen; other symbolsare defined the same as above; P₁, P₂ and R are a group which can beprotected and/or deprotected described in Protective Groups in OrganicSynthesis, Theodora W Green (John Wiley & Sons) etc., for example, R islower alkyl, and the like; P₁ is arylalkyl, and the like; P₂ is loweralkyloxycarbonyl, and the like.

Step 1

Condensing agent such as HATU, WSC.HCl, and the like is added toCompound ba commercially available or prepared by a known method insolvent such as DMF, DMA, NMP, THF, and the like, and Compound bbcommercially available or prepared by a known method and tertiary aminesuch as triethylamine, N-methylmorpholine, pyridine, and the like areadded to the mixture. Compound be can be obtained by reacting at 10° C.to 60° C., preferably 20° C. to 40° C. for 0.1 hours to 24 hours,preferably an hour to 12 hours.

Step 2

Compound bd can be obtained from Compound be by a known deprotectivereaction of an amino-protecting group.

Step 3

Halogenated agent such as bromine, NBS, NCS, NIS, and the like is addedto the mixture containing Compound bd in solvent such asdichloromethane, dichloroethane, acetonitrile, DMF, and the like. WhenHal is bromine, Compound be can be obtained by reacting at −30° C. to50° C., preferably −10° C. to 20° C. for 0.1 hours to 10 hours,preferably 0.5 hours to 2 hours. When Hal is chlorine or iodine,Compound be can be obtained by reacting at 10° C. to 150° C., preferably60° C. to 120° C. for 0.5 hours to 24 hours, preferably an hour to 6hours.

(Production Method 3)

Wherein P₁ is a hydroxy-protecting group; P₂ is an amino-protectinggroup; P₃ is a carboxy-protecting group; Hal is halogen; other symbolsare defined the same as above; P₁, P₂ and P₃ are a group which can beprotected and/or deprotected described in Protective Groups in OrganicSynthesis, Theodora W Green (John Wiley & Sons) etc., for example, P₁ isarylalkyl, and the like; P₂ is lower alkyloxycarbonyl, and the like; P₃is lower alkyl, and the like.

Step 1

Condensing agent such as HATU, WSC.HCl, and the like is added toCompound da prepared by a known method in solvent such as DMF, DMA, NMP,THF, and the like, and Compound db commercially available or prepared bya known method and tertiary amine such as triethylamine,N-methylmorpholine, pyridine, and the like are added to the mixture.Compound de can be obtained by reacting at 10° C. to 60° C., preferably20° C. to 40° C. for 0.1 hours to 24 hours, preferably an hour to 12hours.

Step 2

Compound de can be obtained from Compound de by a known deprotectivereaction of an amino-protecting group.

Step 3

Compound df commercially available or prepared by a known method,tertiary amine such as triethylamine, diisopropylethylamine,N-methylmorpholine, and the like and acetic acid are added to Compoundde in solvent such as toluene, DMF, DMA, NMP, and the like. Compound dgcan be obtained by reacting at 60° C. to 120° C., preferably 80° C. to100° C. for 0.1 hours to 24 hours, preferably an hour to 12 hours.

Step 4

Halogenated agent such as bromine, NBS, NCS, NIS, and the like is addedto Compound dg in solvent such as dichloromethane, dichloroethane,acetonitrile, DMF, and the like. When Hal is bromine, Compound dh can beobtained by reacting at −30° C. to 50° C., preferably −10° C. to 20° C.for 0.1 hours to 10 hours, preferably 0.5 hours to 2 hours. When Hal ischlorine or iodine, Compound dh can be obtained by reacting at 10° C. to150° C., preferably 60° C. to 120° C. for 0.5 hours to 24 hours,preferably an hour to 6 hours.

Step 5

A palladium catalyst such as Pd(PPh₃)₄, Pd(OAc)₂, Pd(PPh₃)₂Cl₂,Pd(dppf)₂Cl₂, Pd(dtbpf), and the like and lower alkylalchol such asethanol, propanol, butanol, and the like are added to Compound dh insolvent such as dioxane, DMF, DME, tetrahydrofuran, and the like or itsreaction mixture. Compound di can be obtained by reacting at 0° C. to150° C., preferably 60° C. to 120° C. for 0.5 hours to 24 hours,preferably an hour to 12 hours under the carbon monoxide atmosphere.

Step 6

Compound dj can be obtained from Compound di by a known deprotectivereaction of a carboxy-protecting group.

The present compound obtained above may be further chemically modifiedto synthesize another compound. In addition, in the above reaction, whena reactive functional group (e.g., OH, COOH, NH₂) is present on a sidechain part, etc., the group may be protected before the reaction and maybe deprotected after the reaction if desired.

Examples of protecting groups (such as amino protecting group, hydroxyprotecting group, and the like) can include protecting groups, such asethoxycarbonyl, t-butoxycarbonyl, acetyl, benzyl, and the like, whichare described in Protective Groups in Organic Synthesis, written by T.W. Greene, John Wiley & Sons Inc. (1991), or the like. Methods for theintroduction and removal of a protecting group are methods commonly usedin synthetic organic chemistry (see, for example, methods described inProtective Groups in Organic Synthesis, written by T. W. Greene, JohnWiley & Sons Inc., (1991), or the like) or can be obtained in accordancetherewith. In addition, a functional group included in each substituentcan be converted by a known method (for example, those described inComprehensive Organic Transformations, written by R. C. Larock (1989),and the like) in addition to the above production methods. Some of thecompounds of the present invention can be used as a syntheticintermediate, further leading to a new derivative. Intermediates andtarget compounds produced in each of the above production methods can beisolated and purified by a purification method commonly used insynthetic organic chemistry, for example, subjecting them toneutralization, filtration, extraction, washing, drying, concentration,recrystallization, any kind of chromatography, or the like. In addition,intermediates can be subjected to a next reaction without furtherpurification.

The present compound is useful, for example, as a medicament such asanti-viral agent and the like. The present compound has remarkableinhibitory activity against virus integrase. Therefore, the presentcompound can be expected to have a preventive or therapeutic effect onvarious diseases caused by a virus which produces at least integrase andincreases at infection in an animal cell; and, for example, it is usefulas an integrase inhibiting agent against retroviruses (e.g., HIV-1,HIV-2, HTLV-1, SIV, FIV, etc.); and useful as an anti-HIV agent and thelike. A preferred compound also has the following characteristics aspharmacokinetics in the body: the blood concentration is high; theduration of an effect is long; the transitivity to tissue is remarkable;and/or the like. In addition, a preferred compound is safe with regardto a side effect.

In addition, the present compound may be used in a combination therapyin combination with an anti-HIV agent having the different actionmechanism such as a reverse transcriptase inhibitor and/or a proteaseinhibiting agent, etc.

Further, the above use includes not only use as a mixture for anti-HIV,but also use as a concomitant agent for increasing the anti-HIV activityof another anti-HIV agent such as cocktail therapy and the like.

In addition, the present compound can be used to prevent infection witha retrovirus vector from spreading into a tissue other than a targettissue, upon use of a retrovirus vector based on HIV or MLV in the fieldof gene therapy. Particularly, when a cell or the like is infected witha vector in vitro and then returned into a body, if the present compoundis administered in advance, unnecessary infection in the body can beprevented.

The present compound can be administered orally or parenterally. In thecase of oral administration, the present compound can be also used as aconventional preparation, for example, as any dosage form of a solidagent such as tablet, powder, granule, capsule, and the like;pharmaceutical solution; oleaginous suspension; liquid such as syrup andelixir; or the like. In the case of parenteral administration, thepresent compound can be used as an aqueous or oleaginous suspendedinjection, or a nasal drop. Upon preparation of it, any conventionalexcipients, binders, lubricants, aqueous solvents, oleaginous solvents,emulsifiers, suspending agents, preservatives, stabilizers and the likemay be used. In addition, as an anti-HIV agent, an oral agent isparticularly preferred. A preparation of the present invention isproduced by combining (e.g. mixing) a therapeutically effective amountof the present compound with a pharmaceutically acceptable carrier ordiluent.

The dose of a compound of the present invention varies depending on anadministration method, the age, weight and condition of a patient, andthe type of a disease. Usually, in the case of oral administration,about 0.05 mg to 3000 mg, preferably about 0.1 mg to 1000 mg, may beadministered per adult daily, if necessary, by dividing the dose. Inaddition, in the case of parenteral administration, about 0.01 mg to1000 mg, preferably about 0.05 mg to 500 mg, is administered per adultdaily.

EXAMPLES

Hereinafter, Examples are described.

Abbreviation Bn: Benzyl DMA; N,N-Dimethylacetamide DMF:N,N-dimethylformamide

HATU: O-(7-Aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

NBS: N-Bromosuccinimide NCS: N-Chlorosuccinimide NIS; N-IodosuccinimideNMP: N-methylpyrrolidone

PdCl₂(dppf); [1, F-Bis(diphenylphosphino)ferrocene]palladium(II)DichloridePd(PPh₃)₄: Tetrakis(triphenylphosphine)palladium(0)TFA: trifluoroacetic acidTHF: tetrahydrofuranWSC.HCl; 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

NMR analysis of each example was performed by 300 MHz or 400 MHz usingDMSO-d₆ or CDCl₃.

In the tables “No.” means Compound No., “Structure” means chemicalstructure, “RT (min)” means retention time (min) in LC/MS: liquid columnchromatography/mass analysis, “[M+H]+” means molecular weight in LC/MS:liquid column chromatography/mass analysis, and “Method” means thefollowing measuring comdition. As for compounds that two type isomersare existed in mobile phase, two peaks may be shown.

(Analytical Method) (A) Column; ACQUITY UPLC® BEH C18 (1.7 μm i.d.2.1×50 mm) (Waters)

Flow rate; 0.8 mL/min;UV detection wavelength; 254 nm;Mobile phases; [A] aqueous solution containing 0.1% formic acid, [13]acetonitrile containing 0.1% formic acid;Gradient; linear gradient of 5% to 100% solvent [13] for 3.5 minutes wasperformed, and 100% solvent [13] was maintained for 0.5 minute.

(B) Column: Shim-pack XR-ODS (2.2 μm, i.d. 50×3.0 mm) (Shimadzu)

Flow rate; 1.6 mL/min;UV detection wavelength; 254 nm;Mobile phases; [A] aqueous solution containing 0.1% formic acid, [B]acetonitrile containing 0.1% formic acid;Gradient; linear gradient of 5% to 100% solvent [B] for 3 minutes wasperformed, and 100% solvent [B] was maintained for 0.5 minute.

Example 1

The following compound was synthesized by a similar procedure to Example1 of Patent Document 15 (WO2013/054862).

TABLE 1 No. Structure RT (min) [M + H]+ Method A-1

1.98 476 A A-2

1.9 462 A A-3

1. 9 462 A A-4

1.95 460.1 A A-5

2.08 476 A A-6

1.77 446 A

TABLE 2 No. Structure RT (min) [M + H]+ Method A-7

1.77 446 A A-8

1.88 460 A A-9

2.0 476 A A-10

1.93 460 A A-11

2.06 476 A A-12

1.94 478.1 A

TABLE 3 No. Structure RT (min) [M + H]+ Method A-13

1.87 460 B A-14

1.80 464 A

The following compound was synthesized by a similar procedure to Example3 of Patent Document 15 (WO2013/054862).

TABLE 4 No. Structure RT (min) [M + H]+ Method A-15

1.55 447 A A-16

1.66 461.2 A A-17

1.77 477.2 A A-18

1.69 463 A A-19

1.55 447 A A-20

1.69 463 A

TABLE 5 No. Structure RT (min) [M + H]+ Method A-21

1.68 461 A A-22

1.81 477 A A-23

1.73 479.1 A A-24

1.76 479.1 A A-25

1.84 495 A A-26

1.89 495 A

TABLE 6 No. Structure RT (min) [M + H]+ Method A-27

1.89 511.2 A A-28

1.77 477.2 A A-29

1.7 481.1 A A-31

1.73 479.2 A A-32

1.67 491.2 A A-33

1.8 477 A

TABLE 7 No. Structure RT (min) [M + H]+ Method A-34

2.07 545 A A-35

1.44 472.1 A A-36

1.77 500 A A-37

1.91 516 A A-38

1.92 491 A A-39

1.73 479 A

Example 2: Synthesis of Compound A-40

Step 1 Synthesis of Compound 1

1 mol/L (2,4-difluorophenyl)magnesium bromide/THF solution (14 mL) wasadded dropwise to THF solution (36 ml) of 5-bromothiazole-2-carbaldehyde(1.81 g, 9.43 mmol) at −78° C. The mixture was stirred for an hour. 1mol/L hydrochloric acid aqueous solution was added to the mixture. Aftercooling to room temperature, the mixture was extracted with ethylacetate. After the organic phase was washed with brine and dried bysodium sulfate anhydrate, the mixture was condensed. Trifluoroaceticacid (10.9 ml) and triethylsilane (5.4 mL) were added to the obtainedresidue. The mixture was stirred at 80° C. for 4 hours. After thereaction mixture was cooled to room temperature, the solvent was removedin vacuo. The obtained crude was purified by silica-gel columnchromatography and eluted by hexane ethyl acetate to give Compound 1(1.41 g, 52%).

MS: m/z=290 [M+H]+

Step 2 Synthesis of Compound 3

Pinacolatodiboron (6.06 g, 23.9 mmol), potassium acetate (2.39 g, 24.3mmol) and PdCl₂ (dppf) CH₂Cl₂ (390 mg, 0.477 mmol) were added to DMFsolution (20 ml) of Compound 2 (2.00 g, 4.77 mmol). The mixture wasstirred at 110° C. for 10 minutes. After the obtained solution wascooled to room temperature, water was added. The mixture was extractedwith ethyl acetate. The organic phase was washed with water twice andbrine solvent, and dried by sodium sulfate anhydrate to remove thesolvent. The residue was suspended to hexane ethyl acetate (40:1, v:v).The obtained solids were filtrated and washed with hexane to giveCompound 3 (1.39 g, 76%).

MS: m/z=385 [M+H]+

Step 3 Synthesis of Compound 4

Compound 1 obtained by Step 1, 2 mol/L sodium carbonate aqueous solution(5210 and PdCl₂ (dppf) CH₂Cl₂ (43 mg, 0.052 mmol) were added to DMFsolution (2 ml) of Compound 3 (200 mg, 0.521 mmol) obtained by Step 2.The mixture was stirred at 110° C. for 90 minutes. After the obtainedsolution was cooled to room temperature, water was added, and themixture was extracted with ethyl acetate. The organic phase was washedwith water twice and dried with sodium sulfate anhydrate to remove thesolvent. The obtained crude was purified by silica-gel columnchromatography and eluted by chloroform methanol to give Compound 4 (142mg, 50%).

MS: m/z=369 [M+H]+

Step 4 Synthesis of Compound A-40

Compound 4 (142 mg, 0.258 mmol) was dissolved to TFA (2 ml). The mixturewas stirred at room temperature for an hour. The obtained reactionsolution was condensed in vacuo. The mixture was diluted with chloroformand washed with sodium hydrogen carbonate aqueous solution and 5% citricacid aqueous solution. The organic phase was dried with sodium sulfateanhydrate. The solvent was removed in vacuo. Ethyl acetate diisopropylether was added to the obtained residue to solidify. The solids werefiltrated to give Compound A-40 (100 mg, 85%). LC/MS (ESI): 1.78 min,found 460 (M+1)

¹H-NMR (DMSO-D₆) δ: 12.29 (1H, s), 8.53 (1H, s), 8.16 (1H, s), 7.57-7.46(1H, m), 7.31-7.22 (1H, m), 7.15-7.04 (1H, m), 5.53-5.43 (1H, m),4.88-4.76 (1H, m), 4.52-4.40 (1H, m), 4.33 (2H, s), 4.30-4.21 (1H, m),4.10-4.01 (1H, m), 3.95-3.86 (1H, m), 2.05-1.98 (1H, m), 1.59-1.50 (1H,m), 1.35 (3H, d, J=7.0 Hz).

The following compound was synthesized by a similar procedure to Example2.

TABLE 8 No. Structure RT (min) [M + H]+ Method A-41

1.95 459 B A-42

1.69 446.2 A A-43

2.07 513.1 B A-44

1.05 429 A

Example 3: Synthesis of Compound A-45

Compound A-45 was synthesized by a similar procedure to Example 2 byusing 2-bromo-4-methylthiazole-5-carbaldehyde as starting material.

LC/MS (ESI): 1.92 min, found 474 (M+1)

¹H-NMR (DMSO-D₆) δ: 12.46 (1H, br s), 8.64 (1H, s), 7.43-7.34 (1H, m),7.27-7.19 (1H, m), 7.10-7.02 (1H, m), 5.50-5.42 (1H, m), 4.87-4.76 (1H,m), 4.66-4.56 (1H, m), 4.44-4.35 (1H, m), 4.13 (2H, s), 4.09-3.98 (1H,m), 3.96-3.86 (1H, m), 2.38 (3H, s), 2.11-1.95 (1H, m), 1.62-1.48 (1H,m), 1.34 (3H, d, J=6.8 Hz).

The following compound was synthesized by a similar procedure to Example3.

TABLE 9 No. Structure RT (min) [M + H]+ Method A-46

1.99 476 A A-47

1.88 460.2 A A-48

2.31 528.2 A

Example 4: Synthesis of Compound A-49

Synthesis of Compound 2

Potassium carbonate (244 mg, 1.77 mmol) and 2,4-difluorobenzyl bromide(0.175 ml, 1.361 mmol) were added to acetone (3 ml) solution of4-bromo-1H-imidazole (200 mg, 1.36 mmol) under nitrogen atmosphere. Themixture was stirred at room temperature for 2 hours. The obtainedreaction solution was filtrated. The filtrate was condensed in vacuo.The obtained crude was purified by silica-gel column chromatography andeluted by hexaneethyl acetate (9:1, v/v) first, and hexaneethyl acetate(1:1, v/v) second. The obtained fractions were condensed to giveCompound 2 (256 mg, 69%).

¹H-NMR (DMSO-d6) δ:5.25 (s, 2H), 7.13 (m, 1H), 7.29-7.35 (m, 2H), 7.40(m, 1H), 7.74 (s, 1H).

Compound A-49 was synthesized by a similar procedure to Example 2 byusing Compound 2 from Compound 1.

LC/MS (ESI): 1.14 min, found 443 (M+1)

The following compound was synthesized by a similar procedure to Example4.

TABLE 10 No. Structure RT (min) [M + H]+ Method A-50

1.28 459 A

Example 5: Synthesis of Compound A-51

Compound A-51 was synthesized from Compound 1 by a similar procedure toExample 2.

LC/MS (ESI): 1.72 min, found 463 (M+1)

Example 6: Synthesis of Compound A-52

Synthesis of Compound 2

Compound 1 (200 mg, 1.07 mmol) was dissolved to acetonitrile (2 ml) inan ice-water bath. Methyl iodide (0.334 ml, 5.34 mmol) was added to themixture. The mixture was stirred at 80° C. for 2 hours. After cooled toroom temperature, the half quantity of the solvent was removed in vacuoto give Compound 2 (328 mg, 93%) by filtration.

¹H-NMR (DMSO-d6) δ:2.63 (s, 1H), 4.23 (s, 1H), 7.19 (m, 1H), 7.36 (m,1H), 7.55 (m, 1H), 11.70 (brs, 1H).

Step 1 Synthesis of Compound 4

Compound 3 (500 mg, 1.30 mmol) was suspended to THF (5 ml) in anice-water bath. Triethylamine (0.19 ml, 1.43 mmol) and isobutylchloroformate (0.36 ml, 2.60 mmol) were added. After the mixture wasstirred at room temperature for an hour, the suspension solution wasadded to THF (3 ml) solution of hydrazine monohydrate (0.64 ml, 13.0mmol) in an ice-water bath. After heated to room temperature, themixture was stirred for 2 hours. After sodium bicarbonate aqueoussolution was added, the mixture was extracted by chloroform twice. Afterthe mixture of extracted solution was dried with sodium sulfateanhydrate, the solvent was removed. The obtained crude was purified bysilica-gel column chromatography (chloroform methanol). The objectivefractions were condensed to give Compound 4 (430.5 mg, 83%).

¹H-NMR (DMSO-d6) δ:1.27 (d, J=6.8 Hz, 3H), 1.50 (dd, J=1.2 Hz, 13.6 Hz,1H), 1.94 (m, 1H), 3.85 (m, 1H), 3.96 (m, 1H), 4.37 (dd, J=6.0 Hz, 14.0Hz, 1H), 4.56 (dd, J=4.5 Hz, 14.0 Hz, 1H), 4.66 (d, J=4.8 Hz, 2H), 4.78(m, 1H), 5.07 (s, 1H), 5.34 (m, 1H), 7.28-7.40 (m, 3H), 7.54-7.60 (m,2H), 8.31 (s, 1H), 8.57 (s, 1H), 10.80 (s, 1H).

Step 2 Synthesis of Compound 5

Compound 2 (282 mg, 0.86 mmol) and triethylamine (0.14 ml, 0.97 mmol)were added to Ethanol (3 ml) solution of Compound 4 (155 mg, 0.39 mmol).The mixture was stirred at 90° C. for 3 hours under heat reflux in anoil bath. Further more, the mixture was irradiated with microwave. Themixture was stirred at 140° C. for 8 minutes. After the obtainedreaction solution was filtrated, the filtrate was condensed in vacuo.The obtained residue was purified by silica-gel column chromatography(chloroformmethanol). The objective fractions were condensed to giveCompound 5 (66 mg, 32%).

¹H-NMR (CDCl₃) δ:1.34 (d, J=5.1 Hz, 3H), 1.51 (dd, J=2.4 Hz, 14.4 Hz,1H), 2.16 (m, 1H), 3.92-3.99 (m, 2H), 4.11 (dd, J=6.0 Hz, 14.4 Hz, 1H),4.13 (s, 2H), 4.22 (dd, J=3.6 Hz, 13.2 Hz, 1H), 5.01 (m, 1H), 5.17 (m,1H), 5.38 (m, 2H), 6.81 (m, 2H), 7.20-7.37 (m, 4H), 7.60-7.64 (m, 2H),8.32 (s, 1H), 8.57 (s, 1H), 13.0 (s, 1H).

Step 3 Synthesis of Compound A-52

Compound 5 (65 mg, 0.39 mmol) was dissolved to TFA (1 ml). The mixturewas stirred at room temperature for an hour. After the obtained reactionsolution was condensed in vacuo, the residue was diluted withchloroform. The mixture was washed with sodium hydrogen carbonateaqueous solution and 5% citric acid aqueous solution. The organic phasewas dried with sodium sulfate anhydrate. The solvent was removed invacuo. Ethyl acetate was added to the obtained residue to solidify. Thesolids were filtrated to give Compound A-52 (45 mg, 84%).

LC/MS (ESI): 1.44 min, found 444 (M+1)

Example 7: Synthesis of Compound A-53

Step 1 Synthesis of Compound 3

Compound 1 (82 mg, 0.41 mmol) was dissolved to dichloromethane (15 mL)and methanol (3 mL). Triethylamine (165 mg, 1.63 mmol), Compound 2 (231mg, 0.61 mmol) and acetic acid (25 mg, 0.41 mmol) were added. Themixture was stirred at 60° C. for 48 hours under heat reflux. Saturatedammonium chloride aqueous solution was added to the reaction mixture.The mixture was extracted with dichloromethane twice. After the organicphase was washed with brine, the mixture was died by sodium sulfateanhydrate. The solvent was removed in vacuo. The obtained residue waspurified by silica-gel column chromatography (methanol chloroform) togive Compound 3 (114 mg, 64%).

LC/MS (ESI): 438[M+1]

Step 2 Synthesis of Compound 4

Compound 3 (114 mg, 0.26 mmol) was dissolved to methanol (5 mL). After 2mol/L sodium hydroxide aqueous solution (0.26 mL, 0.52 mmol) was added,the mixture was stirred at room temperature for 18 hours. Water wasadded to the reaction mixture. After the mixture was adjusted to pH6.8with 1 mol/L hydrochloric acid aqueous solution, the mixture wasextracted with chloroform. After the mixture was washed with brine, themixture was dried with sodium sulfate anhydrate. The solvent was removedin vacuo to give Compound 4 (102 mg, 92%).

LC/MS (ESI): 424[M+1]

Compound A-53 was synthesized by a similar procedure to Example 3 ofPatent Document 15 (WO2013/054862) from Compound 4.

LC/MS (ESI): 500[M+1]

The following compound was synthesized by a similar procedure to Example7.

TABLE 11 No. Structure RT (min) [M + H]+ Method A-54

1.53 488 A A-55

1.44 472.1 A A-56

1.91 516 A

The following compound was synthesized by a similar procedure to any ofthe above procedure.

TABLE 12 No. Structure RT (min) [M + H]+ Method A-57

1.80 487.2 A A-58

1.45 489.2 A A-59

1.17 457.3 A A-60

1.78 486.3 A A-61

1.52 518.3 A

TABLE 13 No. Structure RT (min) [M + H]+ Method A-62

1.50 486.3 A A-63

1.69 473.2 A A-64

1.14 443.3 A A-65

1.74 473.2 A A-66

1.73 473.2 A

TABLE 14 No. Structure RT (min) [M + H]+ Method A-67

1.66 491.2 A A-68

1.60 491.2 A A-69

1.60 491.2 A A-70

1.81 515.2 A A-71

1.87 460.3 B

TABLE 15 No. Structure RT (min) [M + H]+ Method A-72

1.47 444.3 A A-73

1.46 475.2 A A-74

1.46 475.2 A A-75

1.69 505.2 A A-76

1.81 477.1 A

TABLE 16 No. Structure RT (min) [M + H]+ Method A-77

1.76 497.2 A A-78

1.74 497.2 A A-79

1.60 457.2 A A-80

2.06 490.2 A

Example 8: Synthesis of Compound B-1

Step 1

Compound 1 (7.43 g, 23.3 mmol) and Compound 2 (5.00 g, 23.3 mmol) wereadded to toluene (75 ml). The mixture was stirred at 100° C. for 5hours. After the reaction mixture was cooled to room temperature, thesolvent was removed in vacuo. The obtained crude was purified bysilica-gel column chromatography and eluted with n-hexaneethyl acetateto give Compound 3 (7.78 g, 65%).

MS: m/z=515 [M+H]+

Step 2

Compound 3 (7.78 g, 15.1 mmol) obtained by Step 1 was dissolved to 4mol/L hydrochloric acid/ethyl acetate solution (80 ml). The mixture wasstirred at room temperature for 30 minutes. After the solvent wasremoved in vacuo, toluene and trimethylamine were added. The mixture wasstirred at 80° C. for 2 hours. After the reaction mixture was cooled toroom temperature, the solvent was removed in vacuo. The obtained crudewas washed with diethyl ether to give Compound 4 (5.45 g, 94%).

MS: m/z=383 [M+H]+

Step 3

Compound 4 (5.45 g, 14.3 mmol) obtained by Step 2 was dissolved tomethanol (100 ml) and tetrahydrofuran (50 ml). 2 mol/L sodium hydroxideaqueous solution (35.6 ml, 71.3 mmol) was added. The mixture was stirredat room temperature for an hour. After 1 mol/L hydrochloric acid wasadded to the reaction mixture to be acidic, the obtained whiteprecipitate was filtrated. The filtrate was washed with water anddiethyl ether and dried to give Compound 5 (4.89 g, 93%).

MS: m/z=369 [M+H]+

Compound B-1 was synthesized by a similar procedure to Example 3 ofPatent Document 15 (WO2013/054862) from Compound 5.

MS: m/z=445 [M+H]+

The following compound was synthesized by a similar procedure to Example8.

TABLE 17 No. Structure RT (min) [M + H]+ Method B-2

1.70 445 B B-3

1.51 431.1 A B-4

1.59 447.2 A B-5

1.79 461 B B-6

1.80 461 B B-7

1.73 463 B

TABLE 18 No. Structure RT (min) [M + H]+ Method B-8

1.73 463 B B-9

1.61 443 B B-10

1.5 447 B B-11

1.5 447 B

Example 9: Synthesis of Compound B-12

Step 1

Compound 1 (3.00 g, 12.2 mmol) was dissolved to tetrahydrofuran (45 ml).1-hydroxybenzotriazole (1.65 g, 12.2 mmol),1-ethyl-3-(3-dimethylamino)carbodiimide hydrochloride (2.80 g, 14.6mmol), Compound 2 (3.67 g, 14.6 mmol) and N,N-diisopropylethylamine(2.55 ml, 14.6 mmol) were added. The mixture was stirred at roomtemperature for 2 hours. After water was added to the reaction mixture,the mixture was extracted with ethyl acetate. The organic phase waswashed with 1 mol/L hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and water. After the solution was dried withsodium sulfate anhydrate, the solvent was removed to give Compound 3(4.22 g, 78%).

MS: m/z=465 [M+H]+

Step 2

Compound 3 (4.22 g, 9.54 mmol) obtained by Step 1 was dissolved to 4mol/L hydrochloric acid/ethyl acetate solution (45 ml). The mixture wasstirred at room temperature for 30 minutes. After the solvent wasremoved in vacuo, ethanol was added. The reaction mixture was adjustedto basicity with saturated sodium carbonate aqueous solution. Themixture was stirred at 50° C. for 2 hours. After the reaction mixturewas cooled to room temperature, the mixture was extracted withchloroform. The organic phase was dried with sodium sulfate anhydrate.After the solvent was removed in vacuo, the obtained crude wascrystallized with dichloromethane and diisopropyl ether to give Compound4 (2.33 g, 75%).

MS: m/z=325 [M+H]+

Step 3

Compound 4 (2.33 g, 7.18 mmol) obtained by Step 2 was dissolved toN,N-dimethylformamide (30 ml). N-bromosuccinimide (1.34 g, 7.54 mmol)was added. The mixture was stirred at room temperature for 30 minutes.After water was added to the reaction mixture, the mixture was extractedwith dichloromethane. After the organic phase was washed with water, themixture was dried with sodium sulfate anhydrate. After the solvent wasremoved in vacuo, the obtained crude was washed with dichloromethane anddiisopropyl ether to give Compound 5 (2.80 g, 97%).

Compound B-12 was synthesized by a similar procedure to Example 1 ofPatent Document 15 (WO2013/054862) from Compound 5.

The following compound was synthesized by a similar procedure to Example9.

TABLE 19 No. Structure RT (min) [M + H]+ Method B-13

1.67 430   A B-14

1.8  446   A B-15

1.75 430   A B-16

1.87 444   B B-17

1.8  446.2 A B-18

1.98 460   B

TABLE 20 No. Structure RT (min) [M + H]+ Method B-19

1.98 460 B

Compound B-20 was synthesized from Compound A by a similar procedure toExample 2.

TABLE 21 No. Structure RT (min) [M + H]+ Method B-20

1.19 427 A

The following compound was synthesized by a similar procedure to any ofthe above procedure.

TABLE 22 No. Structure RT (min) [M + H]+ Method B-21

1.61 463.1 B B-22

1.65 457.1 B

Example 10: Synthesis of Compound C-1

Compound C-1 was synthesized by a similar procedure to Example 3 ofPatent Document 15 (WO2013/054862) by using Compound 1.

MS: m/z=614.2 [M+H]+

The following compound was synthesized by a similar procedure to Example10.

TABLE 23 No. Structure RT (min) [M + H]+ Method C-2

1.77 478.2 B C-3

1.65 464.3 B C-4

1.88 494   B C-5

2.01 516   A C-6

2.14 532   A C-7

1.74 492   A

TABLE 24 No. Structure RT (min) [M + H]+ Method C-8

1.87 508 A

Example 11: Synthesis of Compound C-10

Compound C-10 was synthesized by a similar procedure to Example 1 ofPatent Document 15 (WO2013/054862) from Compound 1 synthesized by asimilar procedure to Example 145 of Patent Document 13 (WO2010/147068).

LC/MS (ESI): 477 (M+1)

The following compound was synthesized by a similar procedure to Example11.

TABLE 25 No. Structure RT (min) [M + H]+ Method C-11

2.31 505 B C-12

2.12 494 B C-13

1.87 463 B

Example 12: Synthesis of Compound C-14

Step 1

Compound 2 was synthesized by a similar procedure to Compound 177A ofPatent Document 13 (WO2010/147068).

Step 2

4 mol/L hydrochloric acid (ethyl acetate solution, 2.6 ml, 10.4 mmol)was added to ethyl acetate (3 ml) solution of Compound 2 (1.137 g, 2.75mmol). The mixture was stirred at room temperature for 2 hours. Afterthe mixture was neutralized with sodium hydrogen carbonate aqueoussolution, the mixture was extracted with chloroform three times. Afterthe organic phase was dried with sodium sulfate anhydrate, the solventwas removed in vacuo to give Compound 3 (768 mg, 89%).

Step 3

Paraformaldehyde (72 mg, 2.39 mmol) was added to DMF (3.7 ml) solutionof Compound 3 (749 mg, 2.39 mmol). The mixture was stirred at 120° C.for an hour in an oil bath. After cooling to room temperature, thedeposited solids were dissolved to DMF (3.7 ml) and dichloromethane (7.5ml). N-bromosuccinimide (425 mg, 2.39 mmol) was added. After the mixturewas stirred at room temperature for an hour, water was added. Themixture was extracted with ethyl acetate. After the organic phase waswashed with water and brine, the organic phase was dried with sodiumsulfate anhydrate. The solvent was removed in vacuo. After the obtainedsolids were suspended to ethyl acetate/isopropyl ether (1:2), the solidswere filtrated to give Compound 4 (632 mg, 65%).

LC/MS (ESI): 1.30 min. found 404 (M+1)

Step 4

PdCl₂ (dppf).CH₂Cl₂ (121 mg, 0.148 mmol) and triethylamine (1.03 ml,7.42 mmol) were added to n-butanol (6 ml) solution of Compound 4 (600mg, 1.48 mmol) to exchange with carbon monoxide. After the mixture wasstirred at 110° C. for 2 hours under heat reflux in an oil bath, themixture was cooled to room temperature. After insoluble matter wasremoved by filtration, the filtrate was condensed in vacuo. The obtainedresidue was purified by silica-gel column chromatography (chloroformmethanol, 99:1 to 95:5). The objective fractions were condensed in vacuoto give Compound 5 (404 mg, 64%).

LC/MS (ESI): 1.69 min. found 426 (M+1)

Step 5

2 mol/L sodium hydroxide aqueous solution (0.94 ml, 1.88 mmol) was addedto methanol (4 ml) solution of Compound 5 (400 mg, 0.94 mmol). After themixture was stirred at room temperature for 2 hours, 2 mol/Lhydrochloric acid was added. The deposited solids were filtrated to giveCompound 6 (234 mg, 67%).

LC/MS (ESI): 1.50 min. found 370 (M+1)

Compound C-14 was synthesized by a similar procedure to Example 3 ofPatent Document 15 (WO2013/054862) from Compound 6.

LC/MS (ESI): 462 (M+1)

The following compound was synthesized by a similar procedure to Example12.

TABLE 26 No. Structure RT (min) [M + H]+ Method C-15

1.63 446   A C-16

1.48 462   A C-17

1.5  420.1 A C-18

1.53 420.1 A C-19

1.43 432   A

The following compound was synthesized by a similar procedure to any ofthe above procedure.

TABLE 27 No. Structure RT (min) [M + H]+ Method C-20

1.79 464.2 A C-21

1.81 448.2 A C-22

1.90 492.2 A C-23

1.67 434.1 A C-24

1.63 458.1 A

TABLE 28 No. Structure RT (min) [M + H]+ Method C-25

1.52 420.2 A C-26

1.59 464.2 A C-27

1.67 508.2 A C-28

1.58 446.2 A

TABLE 29 No. Structure RT (min) [M + H]+ Method D-1

1.71 503.2 A D-2

1.72 549.1 B D-3

2.10 575.2 B D-4

1.75 563.1 B

Experimental Example 1 (Anti-HIV Activity) (Test Method)

Previously, a series of two-fold dilution on test samples were carriedout in a 96-well plate (50 μL/well). Two plates were made for measuringanti-HIV activity and measuring cytotoxicity. For each agent,measurement in duplicate was carried out. An MT-4 cell suspension of2.5×10̂5/mL was dispensed at 100 μL/well onto the 96-well platecontaining the test samples. An HIV virus solution was dispensed at 50μL/well onto the 96-well plate containing the test samples and the cell.To the plate for measuring cytotoxicity, a culture solution wasdispensed at 50 μL/well. It was mixed by a plate mixer, and thenincubated in a CO₂ incubator for 4 days. The 96-well plate incubated for4 days was observed with the naked eye and under a microscope, and itwas confirmed that there is no problem with virus proliferation andinhibition in the wells of the positive control and the negativecontrol. Thirty microliters of a MTT(3-(4,5-dimethylthiazol-2-O-2,5-diphenyltetrazolium bromide) solutionwas dispensed to each well.

A reaction was allowed to occur in a CO₂ incubator for an hour. Fromeach well, 150 μL of the supernatant was removed such that cells are notsucked. One-hundred and fifty microliters of a cell lysis solution wasadded thereto, and then it was mixed well by a plate mixer until thewhole cells are lysed. The mixed 96-well plates were measured by amicroplate reader at two wavelengths, 560 nm/690 nm. Based on thefollowing calculation formula, 50% HIV inhibition concentration (EC50)was calculated.

EC50=10Z

Z=(50%−Low %)/(High %−Low %)×{log(High conc.)−log(Low conc.)}+log(Lowconc.)

Based on the following calculation formula, 50% cytotoxic concentration(CC50) was calculated.

CC50=10Z

Z=(50%−Low %)/(High %−Low %)×{log(High conc.)−log(Low conc.)}+log(Lowconc.)

Based on the following calculation formula, selectivity index (SI) wascalculated.

SI=CC50/EC50

(Result)

TABLE 30 No. EC50 (nM) A-1 7.8 A-2 2.5 A-3 3.7 A-4 7.4 A-5 8 A-6 1.9 A-76.5 A-8 3.5 A-9 7.1 A-10 4.4 A-11 8.8 A-12 4.9 A-13 6.0 A-14 1.2 A-151.1 A-16 2.1 A-17 2.3 A-18 2.3 A-19 3.1 A-20 3.0 A-21 1.0 A-22 1.7 A-232.6 A-24 4.2 A-25 3.4 A-26 3.8 A-27 3.5 A-28 3.3 A-29 2.1 A-31 2.3 A-3212 A-33 2.5 A-34 13 A-35 2.8 A-36 1.4 A-37 2.3 A-38 2.7 A-39 1.6 A-40 11A-42 10 A-43 3.6 A-44 5.1 A-45 4.1 A-46 3.9 A-47 3.4 A-48 14 A-49 10A-50 12 A-51 6.8 A-52 18 A-53 3.0 A-54 1.6 A-55 1.7 A-56 4.0 A-57 1.7A-58 10 A-59 9.5 A-60 2.0 A-61 4.1 A-62 1.6 A-63 2.0 A-64 1.6 A-65 4.2A-66 7.2 A-67 4.2 A-68 4.6 A-69 5.1 A-70 8.0 A-71 9.3 A-72 8.5 A-73 5.7A-74 12 A-75 10 A-76 4.7 A-77 7.2 A-78 4.6 A-79 15 A-80 6.3 B-1 2.9 B-23.9 B-3 3.7 B-4 5.5 B-5 6.7 B-6 7.5 B-7 2.9 B-8 3.8 B-9 2.0 B-10 10 B-115.9 B-12 11 B-13 7.7 B-14 10 B-15 4.0 B-16 7.7 B-17 5.3 B-18 14 B-19 18B-21 4.0 B-22 3.5

TABLE 31 No. EC50 (nM) C-1 3.4 C-2 1.4 C-3 1.1 C-4 2.1 C-5 3.4 C-6 5.7C-7 2.0 C-8 2.4 C-10 5.8 C-12 8.7 C-13 2.7 C-14 2.2 C-15 1.7 C-16 8.5C-18 2.3 C-19 4.2 C-20 1.7 C-21 1.5 C-22 1.3 C-23 1.2 C-24 2.4 C-25 2.2C-26 1.5 C-27 2.0 C-28 4.8 D-1 3.8 D-2 8.0 D-3 4.8 D-4 4.1

Formulation Example

A term “active ingredient” means the present compound, a tautomerthereof, a pharmaceutically acceptable salt thereof, or a solvatethereof.

Formulation Example 1

A hard gelatin capsule is prepared using the following ingredients:

Dose (mg/capsule) Active ingredient 250 Starch (dried) 200 Magnesiumstearate 10 Total 460 mg

Formulation Example 2

A tablet is prepared using the following ingredients:

Dose (mg/capsule) Active ingredient 250 Cellulose (microcrystalline) 200Silicon dioxide (fumed) 10 Stearic acid 5 Total 665 mg

Ingredients are mixed, and compressed to obtain tablets, each weighing665 mg.

INDUSTRIAL APPLICABILITY

The present compound has integrase inhibitory activity and/or cellproliferation inhibitory activity against viruses, in particular, HIV.Thus, the compound is useful in preventing or treating various diseases,viral infections (e.g., AIDS), and the like in which integraseparticipates.

1. A compound represented by the following formula (I-1) or (I-2), orits pharmaceutically acceptable salt:

wherein Q is a substituted or unsubstituted carbocyclyl or substitutedor unsubstituted heterocyclyl; A ring is a substituted or unsubstitutedheterocycle; D ring is a substituted or unsubstituted heterocycle; R³ isa hydrogen, halogen, hydroxy, substituted or unsubstituted lower alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedlower alkenyl, substituted or unsubstituted lower alkoxy, substituted orunsubstituted lower alkenyloxy, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclyloxy, orsubstituted or unsubstituted amino; R⁸ is a hydrogen, halogen, hydroxy,substituted or unsubstituted lower alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkoxy, substituted or unsubstituted loweralkenyloxy, substituted or unsubstituted aryl, substituted orunsubstituted aryloxy, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclyloxy or substituted orunsubstituted amino; R¹⁴ and R^(X) are each independently, hydrogen,substituted or unsubstituted lower alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkyl lower alkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedlower alkoxy, substituted or unsubstituted lower alkenyloxy, substitutedor unsubstituted aryl, substituted or unsubstituted aryl lower alkyl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclyl lower alkyl,substituted or unsubstituted heterocyclyloxy, substituted orunsubstituted phosphoric acid residue, aryl substituted with substitutedor unsubstituted phosphoric acid residue, hydroxy substituted withsubstituted or unsubstituted phosphoric acid residue, amino substitutedwith substituted or unsubstituted phosphoric acid residue, lower alkylsubstituted with substituted or unsubstituted phosphoric acid residue(wherein a heteroatom group selected from the group consisting of O, S,SO, SO₂, NR⁵, —N═ and ═N— may intervene in the lower alkyl), hydroxy,substituted or unsubstituted amino, substituted or unsubstituted loweralkylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl,substituted or unsubstituted cycloalkyl lower alkylcarbonyl, substitutedor unsubstituted lower alkoxycarbonyl, substituted or unsubstitutedarylcarbonyl, substituted or unsubstituted aryl lower alkylcarbonyl,substituted or unsubstituted aryloxycarbonyl, substituted orunsubstituted heterocyclylcarbonyl, substituted or unsubstitutedheterocyclyl lower alkylcarbonyl, substituted or unsubstitutedheterocyclyloxycarbonyl or substituted or unsubstituted aminocarbonyl;R⁵ is a hydrogen, substituted or unsubstituted lower alkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyllower alkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkoxy, substituted or unsubstituted aryl,substituted or unsubstituted aryl lower alkyl, substituted orunsubstituted aryloxy, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclyl lower alkyl, substituted orunsubstituted heterocyclyloxy, hydroxy, substituted or unsubstitutedamino, substituted or unsubstituted phosphoric acid residue, arylsubstituted with substituted or unsubstituted phosphoric acid residue,hydroxy substituted with substituted or unsubstituted phosphoric acidresidue, amino substituted with substituted or unsubstituted phosphoricacid residue or lower alkyl substituted with substituted orunsubstituted phosphoric acid residue (wherein a heteroatom groupselected from the group consisting of CO, O, S, SO, SO₂, NR^(a) (R^(a)is a hydrogen or lower alkyl), —N═ and ═N— may intervene in the loweralkyl); or R¹⁴ and R^(X) may be taken together with the neighboring atomto form substituted or unsubstituted spiro ring; the broken linerepresents the presence or absence of a bond; when the broken lineadjacent to the carbon atom connected with R^(x) represents the presenceof a bond, R^(x) is absence; when the broken line adjacent to the carbonatom connected with R⁸ represents the presence of a bond, R⁸ is absence;both the broken lines adjacent to the carbon atom connected with R⁸cannot represent the presence of a bond at the same time; and providedthat the following compounds are excluded:


2. The compound represented by the following formula (I-1), or itspharmaceutically acceptable salt according to claim 1:

wherein each symbol is defined above.
 3. The compound or itspharmaceutically acceptable salt according to claim 2, wherein A ring isrepresented by any one of the following rings:

wherein Z¹, Z², Z³, Z⁴ and Z⁵ are each independently CR¹R², CR¹, O, S,SO, SO₂, N or NR¹⁹; or Z¹ and Z³, Z¹ and Z⁴, Z¹ and Z⁵, Z² and Z⁴, Z²and Z⁵, or Z³ and Z⁵ may be taken together to form substituted orunsubstituted (C2-C4) bridge; R¹ and R² are each independently,hydrogen, halogen, substituted or unsubstituted lower alkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyllower alkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkoxy, substituted or unsubstituted loweralkenyloxy, substituted or unsubstituted aryl, substituted orunsubstituted aryl lower alkyl, substituted or unsubstituted aryl oxy,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclyl lower alkyl, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted phosphoric acid residue, aryl substitutedwith substituted or unsubstituted phosphoric acid residue, hydroxysubstituted with substituted or unsubstituted phosphoric acid residue,amino substituted with substituted or unsubstituted phosphoric acidresidue, lower alkyl substituted with substituted or unsubstitutedphosphoric acid residue (wherein a heteroatom group selected from thegroup consisting of O, S, SO, SO₂, NR⁵ (wherein R⁵ is defined as thesame in claim 1), —N═ and ═N— may intervene in the lower alkyl),hydroxy, substituted or unsubstituted amino, substituted orunsubstituted lower alkylcarbonyl, substituted or unsubstitutedcycloalkylcarbonyl, substituted or unsubstituted cycloalkyl loweralkylcarbonyl, substituted or unsubstituted lower alkoxycarbonyl,substituted or unsubstituted aryl carbonyl, substituted or unsubstitutedaryl lower alkylcarbonyl, substituted or unsubstituted aryl oxycarbonyl,substituted or unsubstituted heterocyclylcarbonyl, substituted orunsubstituted heterocyclyl lower alkylcarbonyl, substituted orunsubstituted heterocyclyloxycarbonyl, substituted or unsubstitutedaminocarbonyl, substituted or unsubstituted ureido or substituted orunsubstituted thioureido; or R¹ and R² may be taken together to formoxo, thioxo or substituted or unsubstituted spiro ring; R¹⁹ is ahydrogen, substituted or unsubstituted lower alkyl, substituted orunsubstituted lower alkenyl, substituted or unsubstituted loweralkylcarbonyl or substituted or unsubstituted lower alkyl sulfonyl; thebroken line represents the presence or absence of a bond; and R⁸ isdefined above.
 4. The compound or its pharmaceutically acceptable saltaccording to claim 2, wherein A ring is represented by any one of thefollowing rings:

wherein E ring is substituted or unsubstituted carbocycle or substitutedor unsubstituted heterocycle; Z¹, Z², Z³, Z⁴ and Z⁵ are eachindependently CR¹R², CR¹, C, O, S, SO, SO₂, N or NR¹⁹ (when Z¹, Z², Z³,Z⁴ or Z⁵ is/are constituent atom(s) of E ring, Z¹, Z², Z³, Z⁴ and Z⁵ areeach independently CR¹, C or N); or Z¹ and Z³, Z¹ and Z⁴, Z¹ and Z⁵, Z²and Z⁴, Z² and Z⁵, or Z³ and Z⁵ may be taken together to formsubstituted or unsubstituted (C2-C4) bridge; R¹ and R² are eachindependently hydrogen, halogen, substituted or unsubstituted loweralkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkyl lower alkyl, substituted or unsubstituted loweralkenyl, substituted or unsubstituted lower alkoxy, substituted orunsubstituted lower alkenyloxy, substituted or unsubstituted aryl,substituted or unsubstituted aryl lower alkyl, substituted orunsubstituted aryloxy, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclyl lower alkyl, substituted orunsubstituted heterocyclyloxy, substituted or unsubstituted phosphoricacid residue, aryl substituted with substituted or unsubstitutedphosphoric acid residue, hydroxy substituted with substituted orunsubstituted phosphoric acid residue, amino substituted withsubstituted or unsubstituted phosphoric acid residue, lower alkylsubstituted with substituted or unsubstituted phosphoric acid residue(wherein a heteroatom group selected from the group consisting of O, S,SO, SO₂, NR⁵ (wherein R⁵ is defined as the same in claim 1), —N═ and ═N—may intervene in the lower alkyl), hydroxy, substituted or unsubstitutedamino, substituted or unsubstituted lower alkylcarbonyl, substituted orunsubstituted cycloalkylcarbonyl, substituted or unsubstitutedcycloalkyl lower alkylcarbonyl, substituted or unsubstituted loweralkoxycarbonyl, substituted or unsubstituted arylcarbonyl, substitutedor unsubstituted aryl lower alkylcarbonyl, substituted or unsubstitutedaryloxycarbonyl, substituted or unsubstituted heterocyclylcarbonyl,substituted or unsubstituted heterocyclyl lower alkylcarbonyl,substituted or unsubstituted heterocyclyloxycarbonyl, substituted orunsubstituted aminocarbonyl, substituted or unsubstituted ureido orsubstituted or unsubstituted thioureido; or R¹ and R² may be takentogether to form oxo, thioxo or substituted or unsubstituted spiro ring;R¹⁹ is a hydrogen, substituted or unsubstituted lower alkyl, substitutedor unsubstituted lower alkenyl, substituted or unsubstituted loweralkylcarbonyl or substituted or unsubstituted lower alkyl sulfonyl; R⁸is defined above; and the broken line represents the presence or absenceof a bond.
 5. The compound or its pharmaceutically acceptable saltaccording to claim 4, wherein E ring is substituted or unsubstituted 4-to 7-membered carbocycle or substituted or unsubstituted 4- to7-membered heterocycle.
 6. The compound represented by the followingformula (I-1-1) or (I-2-1), or its pharmaceutically acceptable saltaccording to claim 2:

wherein X is CR^(9a)R^(9b), NR¹⁰, O or S; R^(5a), R^(5b), R^(6a),R^(6b), R^(7a), R^(7b), R⁸, R^(9a), R^(9b) and R¹⁰ are eachindependently, hydrogen, halogen, substituted or unsubstituted loweralkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkyl lower alkyl, substituted or unsubstituted loweralkenyl, substituted or unsubstituted lower alkoxy, substituted orunsubstituted lower alkenyloxy, substituted or unsubstituted aryl,substituted or unsubstituted aryl lower alkyl, substituted orunsubstituted aryloxy, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclyl lower alkyl, substituted orunsubstituted heterocyclyloxy, substituted or unsubstituted phosphoricacid residue, aryl substituted with substituted or unsubstitutedphosphoric acid residue, hydroxy substituted with substituted orunsubstituted phosphoric acid residue, amino substituted withsubstituted or unsubstituted phosphoric acid residue, lower alkylsubstituted with substituted or unsubstituted phosphoric acid residue(wherein a heteroatom group selected from the group consisting of O, S,SO, SO₂, NR⁵ (wherein R⁵ is defined as the same in claim 1), —N═ and ═N—may intervene in the lower alkyl), hydroxy, substituted or unsubstitutedamino, substituted or unsubstituted lower alkylcarbonyl, substituted orunsubstituted cycloalkylcarbonyl, substituted or unsubstitutedcycloalkyl lower alkylcarbonyl, substituted or unsubstituted loweralkoxycarbonyl, substituted or unsubstituted arylcarbonyl, substitutedor unsubstituted aryl lower alkylcarbonyl, substituted or unsubstitutedaryloxycarbonyl, substituted or unsubstituted heterocyclylcarbonyl,substituted or unsubstituted heterocyclyl lower alkylcarbonyl,substituted or unsubstituted heterocyclyloxycarbonyl, substituted orunsubstituted aminocarbonyl, substituted or unsubstituted ureido orsubstituted or unsubstituted thioureido; R^(5a) and R^(5b), R^(6a) andR^(6b), R^(7a) and R^(7b), and/or R^(9a) and R^(9b) may be takentogether to form oxo, thioxo or substituted or unsubstituted spiro ring;or R^(5b) and R^(6b), R^(6b) and R^(7b), and/or R^(7b) and R^(9b) may betaken together with neighboring atoms to form substituted orunsubstituted carbocycle or substituted or unsubstituted heterocycleand/or R^(5b) and R^(7b), R^(5b) and R⁸, R^(5b) and R^(9b), R^(6b) andR⁸, R^(6b) and R^(9b), or R^(7b) and R⁸ may be taken together to formsubstituted or unsubstituted (C2-C4) bridge; or R^(5b) and R¹⁰ may betaken together with neighboring atoms to form substituted orunsubstituted heterocycle or R^(6b) and R¹⁰, or R^(7b) and R¹⁰ may betaken together to form substituted or unsubstituted (C2-C4) bridge;R^(x) is a hydrogen; the other symbols are defined above.
 7. Thecompound or its pharmaceutically acceptable salt according to claim 6,wherein X is CR^(9a)R^(9b), O or S.
 8. The compound or itspharmaceutically acceptable salt according to claim 6, wherein R^(5a) ishydrogen, halogen, hydroxy, substituted or unsubstituted lower alkyl orsubstituted or unsubstituted lower alkoxy.
 9. The compound or itspharmaceutically acceptable salt according to claim 6, wherein R^(5b) ishydrogen.
 10. The compound or its pharmaceutically acceptable saltaccording to claim 6, wherein R^(6a) is a hydrogen, halogen, hydroxy,substituted or unsubstituted lower alkyl or substituted or unsubstitutedlower alkoxy.
 11. The compound or its pharmaceutically acceptable saltaccording to claim 6, wherein R^(6b) is hydrogen.
 12. The compound orits pharmaceutically acceptable salt according to claim 6, whereinR^(7a) is a hydrogen, halogen, hydroxy, substituted or unsubstitutedlower alkyl or substituted or unsubstituted lower alkoxy.
 13. Thecompound or its pharmaceutically acceptable salt according to claim 6,wherein R^(7b) is hydrogen.
 14. The compound or its pharmaceuticallyacceptable salt according to claim 6, wherein R⁸ is hydrogen.
 15. Thecompound or its pharmaceutically acceptable salt according to claim 6,wherein R^(9a) is a hydrogen, halogen, hydroxy, substituted orunsubstituted lower alkyl or substituted or unsubstituted lower alkoxy.16. The compound or its pharmaceutically acceptable salt according toclaim 6, wherein R^(9b) is hydrogen.
 17. The compound represented by anyone of the following formula, or its pharmaceutically acceptable saltaccording to claim 1:

wherein each Q is defined above.
 18. The compound represented by any oneof the following formula, or its pharmaceutically acceptable saltaccording to claim 1:

wherein each Q is defined above.
 19. The compound represented by thefollowing formula (I-2) or its pharmaceutically acceptable saltaccording to claim 1:

wherein each symbol is defined above.
 20. A compound represented by thefollowing formula (I-3), or its pharmaceutically acceptable salt:

wherein Q is substituted or unsubstituted carbocyclyl or substituted orunsubstituted heterocyclyl; the broken line represents the presence orabsence of a bond; when either one of B¹ and B² is CR²⁰R²¹ and the otheris NR²², the broken line represents the absence of a bond; and R²¹ andR²² may be taken together with the neighboring atoms to form substitutedor unsubstituted heterocycle; when B² is NR²², R⁴ and R²² may be takentogether with the neighboring atoms to form substituted or unsubstitutedheterocycle; when B² is CR²⁰, R²¹, R⁴ and R²¹ may be taken together withthe neighboring atoms to form substituted or unsubstituted heterocycle;or when either one of B¹ and B² is CR²³ and the other is N, the brokenline represents the presence of a bond; when B² is CR²³, R⁴ and R²³ maybe taken together with the neighboring atoms to form substituted orunsubstituted heterocycle; R²⁰, R²¹, R²² and R²³ are each independently,hydrogen, halogen, substituted or unsubstituted lower alkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyllower alkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkoxy, substituted or unsubstituted loweralkenyloxy, substituted or unsubstituted aryl, substituted orunsubstituted aryl lower alkyl, substituted or unsubstituted aryloxy,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclyl lower alkyl, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted phosphoric acid residue, aryl substitutedwith substituted or unsubstituted phosphoric acid residue, hydroxysubstituted with substituted or unsubstituted phosphoric acid residue,amino substituted with substituted or unsubstituted phosphoric acidresidue, lower alkyl substituted with substituted or unsubstitutedphosphoric acid residue (wherein a heteroatom group selected from thegroup consisting of O, S, SO, SO₂, NR⁵ (wherein R⁵ is independentlyselected from the same substituent group as R⁴), —N═ and ═N— mayintervene in the lower alkyl), hydroxy, substituted or unsubstitutedamino, substituted or unsubstituted lower alkylcarbonyl, substituted orunsubstituted cycloalkylcarbonyl, substituted or unsubstitutedcycloalkyl lower alkylcarbonyl, substituted or unsubstituted loweralkoxycarbonyl, substituted or unsubstituted arylcarbonyl, substitutedor unsubstituted aryl lower alkylcarbonyl, substituted or unsubstitutedaryloxycarbonyl, substituted or unsubstituted heterocyclyl carbonyl,substituted or unsubstituted heterocyclyl lower alkyl carbonyl,substituted or unsubstituted heterocyclyloxycarbonyl, substituted orunsubstituted aminocarbonyl, substituted or unsubstituted ureido orsubstituted or unsubstituted thioureido; R³ is hydrogen, halogen,hydroxy, substituted or unsubstituted lower alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl,substituted or unsubstituted lower alkoxy, substituted or unsubstitutedlower alkenyloxy, substituted or unsubstituted aryl, substituted orunsubstituted aryloxy, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclyloxy or substituted orunsubstituted amino; R⁴ is hydrogen, substituted or unsubstituted loweralkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkyl lower alkyl, substituted or unsubstituted loweralkenyl, substituted or unsubstituted lower alkoxy, substituted orunsubstituted aryl, substituted or unsubstituted aryl lower alkyl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heterocyclyl lower alkyl,substituted or unsubstituted heterocyclyloxy, hydroxy, substituted orunsubstituted amino, substituted or unsubstituted phosphoric acidresidue, aryl substituted with substituted or unsubstituted phosphoricacid residue, hydroxy substituted with substituted or unsubstitutedphosphoric acid residue, amino substituted with substituted orunsubstituted phosphoric acid residue or lower alkyl substituted withsubstituted or unsubstituted phosphoric acid residue (wherein aheteroatom group selected from the group consisting of CO, O, S, SO,SO₂, NR^(a) (R^(a) is hydrogen or lower alkyl), —N═ and ═N— mayintervene in the lower alkyl); and provided that the compounds whereinB¹ is NR²², the broken line represents the absence of a bond, and R⁴ isunsubstituted ethyl or unsubstituted isopropyl are excluded.
 21. Thecompound represented by the following formula (I-3-1), or itspharmaceutically acceptable salt according to claim 20:

wherein F ring is substituted or unsubstituted heterocycle; B¹ isCR²⁰R²¹, N or NR²²; when B¹ is CR²⁰R²¹, the broken line represents theabsence of a bond, and B² is N; when B¹ is N, the broken line representsthe presence of a bond, and B² is C; when B¹ is NR²²; the broken linerepresents the absence of a bond, and B² is CR²⁰; and the other symbolsare defined above.
 22. The compound or its pharmaceutically acceptablesalt according to claim 20, wherein F ring is represented by any one ofthe following rings:

wherein Z¹, Z², Z³, Z⁴ and Z⁵ are each independently CR¹R², CR¹, O, S,SO, SO₂, N or NR¹⁹; or Z¹ and Z³, Z¹ and Z⁴, Z¹ and Z⁵, Z² and Z⁴, Z²and Z⁵, or Z³ and Z⁵ may be taken together to form substituted orunsubstituted (C2-C4) bridge; R¹ and R² are each independently,hydrogen, halogen, substituted or unsubstituted lower alkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyllower alkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkoxy, substituted or unsubstituted loweralkenyloxy, substituted or unsubstituted aryl, substituted orunsubstituted aryl lower alkyl, substituted or unsubstituted aryloxy,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclyl lower alkyl, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted phosphoric acid residue, aryl substitutedwith substituted or unsubstituted phosphoric acid residue, hydroxysubstituted with substituted or unsubstituted phosphoric acid residue,amino substituted with substituted or unsubstituted phosphoric acidresidue, lower alkyl substituted with substituted or unsubstitutedphosphoric acid residue (wherein a heteroatom group selected from thegroup consisting of O, S, SO, SO₂, NR⁵ (wherein R⁵ is defined as thesame in claim 20), —N═ and ═N— may intervene in the lower alkyl),hydroxy, substituted or unsubstituted amino, substituted orunsubstituted lower alkylcarbonyl, substituted or unsubstitutedcycloalkylcarbonyl, substituted or unsubstituted cycloalkyl loweralkylcarbonyl, substituted or unsubstituted lower alkoxycarbonyl,substituted or unsubstituted arylcarbonyl, substituted or unsubstitutedaryl lower alkylcarbonyl, substituted or unsubstituted aryloxycarbonyl,substituted or unsubstituted heterocyclylcarbonyl, substituted orunsubstituted heterocyclyl lower alkylcarbonyl, substituted orunsubstituted heterocyclyloxycarbonyl, substituted or unsubstitutedaminocarbonyl, substituted or unsubstituted ureido or substituted orunsubstituted thioureido; or R¹ and R² may be taken together to formoxo, thioxo or substituted or unsubstituted spiro ring; R¹⁹ is hydrogen,substituted or unsubstituted lower alkyl, lower alkenyl, substituted orunsubstituted lower alkylcarbonyl or substituted or unsubstituted loweralkylsulfonyl; the broken line represents the presence or absence of abond; and the other symbols are defined above.
 23. The compound or itspharmaceutically acceptable salt according to claim 21, wherein F ringis represented by any one of the following rings:

wherein H ring is substituted or unsubstituted carbocycle or substitutedor unsubstituted heterocycle; Z¹, Z², Z³, Z⁴ and Z⁵ are eachindependently CR¹R², CR¹, C, O, S, SO, SO₂, N or N¹⁹ (when Z¹, Z², Z³,Z⁴ or Z⁵ is/are constituent atom(s) of H ring, Z¹, Z², Z³, Z⁴ and Z⁵ areeach independently CR¹, C or N); or Z¹ and Z³, Z¹ and Z⁴, Z¹ and Z⁵, Z²and Z⁴, Z² and Z⁵, or Z³ and Z⁵ may be taken together to formsubstituted or unsubstituted (C2-C4) bridge; R¹ and R² are eachindependently, hydrogen, halogen, substituted or unsubstituted loweralkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkyl lower alkyl, substituted or unsubstituted loweralkenyl, substituted or unsubstituted lower alkoxy, substituted orunsubstituted lower alkenyloxy, substituted or unsubstituted aryl,substituted or unsubstituted aryl lower alkyl, substituted orunsubstituted aryloxy, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclyl lower alkyl, substituted orunsubstituted heterocyclyloxy, substituted or unsubstituted phosphoricacid residue, aryl substituted with substituted or unsubstitutedphosphoric acid residue, hydroxy substituted with substituted orunsubstituted phosphoric acid residue, amino substituted withsubstituted or unsubstituted phosphoric acid residue, lower alkylsubstituted with substituted or unsubstituted phosphoric acid residue(wherein a heteroatom group selected from the group consisting of O, S,SO, SO₂, NR⁵ (wherein R⁵ is defined as the same in claim 20), —N═ and═N— may intervene in the lower alkyl), hydroxy, substituted orunsubstituted amino, substituted or unsubstituted lower alkylcarbonyl,substituted or unsubstituted cycloalkylcarbonyl, substituted orunsubstituted cycloalkyl lower alkylcarbonyl, substituted orunsubstituted lower alkoxycarbonyl, substituted or unsubstitutedarylcarbonyl, substituted or unsubstituted aryl lower alkylcarbonyl,substituted or unsubstituted aryloxycarbonyl, substituted orunsubstituted heterocyclylcarbonyl, substituted or unsubstitutedheterocyclyl lower alkylcarbonyl, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstituted aminocarbonyl,substituted or unsubstituted ureido or substituted or unsubstitutedthioureido; or R¹ and R² may be taken together to form oxo, thioxo orsubstituted or unsubstituted spiro ring; R¹⁹ is hydrogen, substituted orunsubstituted lower alkyl, lower alkenyl, substituted or unsubstitutedlower alkylcarbonyl or substituted or unsubstituted lower alkylsulfonyl; the broken line represents the presence or absence of a bond;and the other symbols are defined above.
 24. The compound or itspharmaceutically acceptable salt according to claim 23, wherein H ringis substituted or unsubstituted 4- to 7-membered carbocycle orsubstituted or unsubstituted 4- to 7-membered heterocycle.
 25. Thecompound represented by the following formula (I-3-2), or itspharmaceutically acceptable salt according to claim 20:

wherein G ring is substituted or unsubstituted carbocycle or substitutedor unsubstituted heterocycle; B¹ is CR²¹ or N; when B¹ is CR²¹, B² is N;when B¹ is N, B² is CR²¹; and the other symbols are defined above. 26.The compound or its pharmaceutically acceptable salt according to claim25, wherein G ring is represented by any one of the following rings:


27. The compound or its pharmaceutically acceptable salt according toclaim 20, wherein B² is N or NR²² (wherein R²² is defined above; provisowhen the broken line represents the presence of a bond or when B² isconstituent atom of F ring or G ring, B² is N).
 28. The compoundrepresented by the following formula (I-3-3) or (I-3-4), or itspharmaceutically acceptable salt according to claim 20:

wherein R¹¹, R^(12a), R^(12b) and R¹³ are each independently, hydrogen,halogen, substituted or unsubstituted lower alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl loweralkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkoxy, substituted or unsubstituted loweralkenyloxy, substituted or unsubstituted aryl, substituted orunsubstituted aryl lower alkyl, substituted or unsubstituted aryloxy,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedheterocyclyl lower alkyl, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted phosphoric acid residue, aryl substitutedwith substituted or unsubstituted phosphoric acid residue, hydroxysubstituted with substituted or unsubstituted phosphoric acid residue,amino substituted with substituted or unsubstituted phosphoric acidresidue, lower alkyl substituted with substituted or unsubstitutedphosphoric acid residue (wherein a heteroatom group selected from thegroup consisting of O, S, SO, SO₂, NR⁵ (wherein R⁵ is defined as thesame in claim 20), —N═ and ═N— may intervene in the lower alkyl),hydroxy, substituted or unsubstituted amino, substituted orunsubstituted lower alkylcarbonyl, substituted or unsubstitutedcycloalkylcarbonyl, substituted or unsubstituted cycloalkyl lower alkylcarbonyl, substituted or unsubstituted lower alkoxycarbonyl, substitutedor unsubstituted arylcarbonyl, substituted or unsubstituted aryl loweralkylcarbonyl, substituted or unsubstituted aryloxycarbonyl, substitutedor unsubstituted heterocyclylcarbonyl, substituted or unsubstitutedheterocyclyl lower alkylcarbonyl, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstituted aminocarbonyl,substituted or unsubstituted ureido or substituted or unsubstitutedthioureido; or R^(12a) and R^(12b) may be taken together to form oxo,thioxo; when the compound is represented by formula (I-3-4), R^(12a) andR^(12b) may be taken together to form substituted or unsubstituted spiroring; and Q is defined above.
 29. The compound represented by thefollowing formula (I-3-5) or (I-3-6), or its pharmaceutically acceptablesalt according to claim 20:

wherein X is CR^(18a)R^(18b), NR²⁴, O or S; R^(15a), R^(15b), R^(16a),R^(16b), R^(17a), R^(17b), R^(18a), R^(18b) and R²⁴ are eachindependently, hydrogen, halogen, substituted or unsubstituted loweralkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkyl lower alkyl, substituted or unsubstituted loweralkenyl, substituted or unsubstituted lower alkoxy, substituted orunsubstituted lower alkenyloxy, substituted or unsubstituted aryl,substituted or unsubstituted aryl lower alkyl, substituted orunsubstituted aryloxy, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclyl lower alkyl, substituted orunsubstituted heterocyclyloxy, substituted or unsubstituted phosphoricacid residue, aryl substituted with substituted or unsubstitutedphosphoric acid residue, hydroxy substituted with substituted orunsubstituted phosphoric acid residue, amino substituted withsubstituted or unsubstituted phosphoric acid residue, lower alkylsubstituted with substituted or unsubstituted phosphoric acid residue(wherein a heteroatom group selected from the group consisting of O, S,SO, SO₂, NR⁵ (wherein R⁵ is defined as the same in claim 20), —N═ and═N— may intervene in the lower alkyl), hydroxy, substituted orunsubstituted amino, substituted or unsubstituted lower alkylcarbonyl,substituted or unsubstituted cycloalkylcarbonyl, substituted orunsubstituted cycloalkyl lower alkylcarbonyl, substituted orunsubstituted lower alkoxycarbonyl, substituted or unsubstitutedarylcarbonyl, substituted or unsubstituted aryl lower alkylcarbonyl,substituted or unsubstituted aryloxycarbonyl, substituted orunsubstituted heterocyclylcarbonyl, substituted or unsubstitutedheterocyclyl lower alkylcarbonyl, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstituted aminocarbonyl,substituted or unsubstituted ureido or substituted or unsubstitutedthioureido; or R^(15a) and R^(15b), R^(15a) and R^(15b), R^(17a) andR^(17b), or R^(18a) and R^(18b) may be taken together to form oxo,thioxo or substituted or unsubstituted spiro ring; or R^(15b) andR^(16b), R^(16b) and R^(18b), and/or R^(17b) and R^(18b) may be takentogether to form substituted or unsubstituted carbocycle or substitutedor unsubstituted heterocycle; or R^(15b) and R^(17b), R^(15b) andR^(18b), or R^(16b) and R^(17b) may be taken together to formsubstituted or unsubstituted (C2-C4) bridge; or R^(16b) and R²⁴, orR^(17b) and R²⁴ may be taken together to form substituted orunsubstituted heterocycle; or R^(15b) and R²⁴ may be taken together toform substituted or unsubstituted (C2-C4) bridge; and the other symbolsare defined above.
 30. The compound or its pharmaceutically acceptablesalt according to claim 29, wherein R^(15a) is hydrogen or substitutedor unsubstituted lower alkyl.
 31. The compound or its pharmaceuticallyacceptable salt according to claim 29, wherein R^(15b) is hydrogen. 32.The compound or its pharmaceutically acceptable salt according to claim29, wherein R^(16a) is hydrogen or substituted or unsubstituted loweralkyl.
 33. The compound or its pharmaceutically acceptable saltaccording to claim 29, wherein R^(16b) is hydrogen.
 34. The compound orits pharmaceutically acceptable salt according to claim 29, whereinR^(17a) is hydrogen or substituted or unsubstituted lower alkyl.
 35. Thecompound or its pharmaceutically acceptable salt according to claim 29,wherein R^(17b) is hydrogen.
 36. The compound or its pharmaceuticallyacceptable salt according to claim 29, wherein R^(18a) is hydrogen orsubstituted or unsubstituted lower alkyl.
 37. The compound or itspharmaceutically acceptable salt according to claim 29, wherein R^(18b)is hydrogen.
 38. The compound or its pharmaceutically acceptable saltaccording to claim 29, wherein R²⁴ is hydrogen or substituted orunsubstituted lower alkyl.
 39. The compound represented by any one ofthe following formula, or its pharmaceutically acceptable salt accordingto claim 20:

wherein each Q is defined above.
 40. The compound or itspharmaceutically acceptable salt according to claim 1, wherein Q issubstituted or unsubstituted heterocyclyl.
 41. The compound or itspharmaceutically acceptable salt according to claim 1, wherein Q issubstituted or unsubstituted 5- to 7-membered monocyclic heterocyclyl.42. The compound or its pharmaceutically acceptable salt according toclaim 1, wherein Q is represented by any one of the following formula:


43. The compound or its pharmaceutically acceptable salt according toclaim 1, wherein Q is carbocyclyl or heterocyclyl substituted with thesame or different, 1 to 4 substituent(s) selected from Substituent groupA: Substituent group A: lower alkyl, lower alkoxy, halogen, halogenatedlower alkyl, halogenated lower alkoxy, and the group of formula (B):

wherein X^(A) is a group selected from the following group: X^(A1): asingle bond; X^(A2): a group selected from C(═O) and C(═S); X^(A4): aheteroatom group selected from O, S, SO, SO₂, and N(R^(1′)) whereinR^(1′) is hydrogen or lower alkyl; X^(A4): a group formed by linking thesame or different, two or more groups selected from X^(A2) and X^(A3);X^(A5): a group selected from —N═N—, —C(R^(1′))═N—, or —N═C(R^(1′))—wherein R^(1′) is hydrogen or lower alkyl; X^(A6): substituted orunsubstituted lower alkylene or substituted or unsubstituted loweralkenylene; X^(A7): X^(A6) intervened by one or any two or more groupsselected from X^(A2), X^(A3), X^(A4), and X^(A5); X^(A8): a groupCR^(1′)R^(2′) wherein R^(1′) and R^(2′) are taken together withneighboring atoms to form carbocycle or heterocycle; and X^(A9): aspacer consisting of any combination of X^(A1) to X^(A8); R is a groupindependently selected from the following groups: (1) lower alkyl, (2)lower alkoxy, (B) halogen, (4) halogenated lower alkyl, (5) halogenatedlower alkoxy, and (6) lower cycloalkyl; and m is an integer of 0 to 5.44. The compound or its pharmaceutically acceptable salt according toclaim 1, wherein Q is represented by the following formula (1) or (2):

wherein X^(A) is a group selected from the following group: X^(A1): asingle bond; X^(A2): a group selected from C(═O) and C(═S); X^(A3): aheteroatom group selected from O, S, SO, SO₂, and N(R^(1′)) whereinR^(1′) is hydrogen or lower alkyl; X^(A4): a group formed by linking thesame or different, two or more groups selected from X^(A2) and X^(A3);X^(A5): a group selected from —N═N—, —C(R^(1′))═N—, or —N═C(R^(1′))—wherein R^(1′) is hydrogen or lower alkyl; X^(A6): substituted orunsubstituted lower alkylene or substituted or unsubstituted loweralkenylene; X^(A7): X^(A6) intervened by one or any two or more groupsselected from X^(A2), X^(A3), X^(A4), and X^(A5); X^(A8): a groupCR^(1′)R^(2′) wherein R^(1′) and R^(2′) are taken together withneighboring atoms to form carbocycle or heterocycle; and X^(A9): aspacer consisting of any combination of X^(A1) to X^(A8); R is a groupindependently selected from the following groups: (1) lower alkyl, (2)lower alkoxy, (B) halogen, (4) halogenated lower alkyl, (5) halogenatedlower alkoxy, and (6) lower cycloalkyl; and m is an integer of 0 to 5.45. The compound or its pharmaceutically acceptable salt according toclaim 43, wherein X^(A) is lower alkylene; R is independently loweralkoxy, halogen or halogenated lower alkyl; and m is 1 or
 2. 46. Thecompound or its pharmaceutically acceptable salt according to claim 1,wherein Q is substituted or unsubstituted carbocyclyl or substituted orunsubstituted heterocyclyl, provided that the following compounds areexcluded:


47. The compound or its pharmaceutically acceptable salt according toclaim 1, wherein Q is represented by any one of the following groups:


48. The compound represented by any one of the following formula (I-1′),(I-2′) or (I-3′), or its pharmaceutically acceptable salt:

wherein Y is represented by any one of the following group:

wherein R^(Y) is substituted or unsubstituted alkyl; and the othersymbols are defined in claim
 1. 49. A pharmaceutical compositioncomprising the compound according to claim 1, or a pharmaceuticallyacceptable salt thereof.
 50. The pharmaceutical composition according toclaim 49, which has anti-HIV activity.
 51. The pharmaceuticalcomposition according to claim 49, which has an HIV integrase inhibitoryactivity.
 52. A method for treating or preventing AIDS by administeringthe compound of claim 1 to human or animals, or a pharmaceuticallyacceptable salt thereof.
 53. The compound of claim 1, or apharmaceutically acceptable salt thereof for medical treatment.
 54. Useof the compound of claim 1, or its pharmaceutically acceptable salt forthe manufacture of a therapeutic or preventive agent for AIDS.